EP3178465A1 - Verfahren zur behandlung von kahlköpfigkeit und zur förderung des haarwuchses - Google Patents

Verfahren zur behandlung von kahlköpfigkeit und zur förderung des haarwuchses Download PDF

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EP3178465A1
EP3178465A1 EP16195263.5A EP16195263A EP3178465A1 EP 3178465 A1 EP3178465 A1 EP 3178465A1 EP 16195263 A EP16195263 A EP 16195263A EP 3178465 A1 EP3178465 A1 EP 3178465A1
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Prior art keywords
hair
hair growth
skin
promoting agent
treatment
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EP16195263.5A
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English (en)
French (fr)
Inventor
Shikha P. Barman
William D. Ju
Scott C. Kellogg
Stephen M. Prouty
Eric Schweiger
Seth Lederman
Mary Osbakken
Alan D. Schinazi
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Follica Inc
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Follica Inc
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Definitions

  • the invention relates to methods of treating baldness, treating alopecia, promoting hair growth, and/or promoting hair follicle development and/or activation on an area of the skin of a subject (for example, a human) by subjecting said area of the skin to integumental perturbation.
  • Integumental perturbation can be used in combination with other treatments for promoting hair growth.
  • the invention provides devices for integumental perturbation for promoting hair growth, and provides pharmaceutical compositions for use in combination with integumental perturbation for promoting hair growth.
  • the skin of an adult human is essentially covered with hair follicles and contains approximately five million hair follicles, with approximately 100,000 - 150,000 covering the scalp.
  • the portions of human skin that lack visible hair contain, for the most part, hair follicles that produce "vellus hair” while certain other hair follicles may contain or produce no hair (see Figure 1 ).
  • hair follicles that produce "vellus hair” while certain other hair follicles may contain or produce no hair (see Figure 1 ).
  • terminal hair Only a minority of human hair follicles produce a hair fiber that can be readily appreciated visibly (a "terminal hair") and these specialized follicles are localized on specific regions of skin; on the normal scalp, terminal hair follicles typically outnumber vellus hair follicles by 7:1. Accordingly, both the presence and absence of visible hair on human non-glaborous skin is mediated by regulation of activity of specialized follicles.
  • Hair follicles and particularly human hair follicles, are crypt structures comprised of distinct components, each comprised of several different specialized cells (see Figures 2 and 3 ).
  • the vast majority of hair follicles contain units called sebaceous glands (which produce sebum).
  • Some hair follicles have apocrine glands attached to them, and are located in the axilla and other specific areas of the body.
  • the structures of the hair follicle include the follicular papilla (FP) and the germinative epithelium (GE) (together, the bulb).
  • the FP is comprised of mesenchymal cells (and connective tissue).
  • the other cells of the follicle are epithelial and include at least 8 cellular lineages including the outer root sheath (ORS), the companion layer (CL), the internal root sheath Henle's layer (He), internal root sheath Huxley's layer (Hu), the cuticle of the internal root sheath (Csth), the cuticle of the hair shaft (Csft), the cortex of the hair shaft, and the medulla of the shaft (Med).
  • ORS outer root sheath
  • CL the companion layer
  • He internal root sheath Henle's layer
  • Csth internal root sheath Huxley's layer
  • Csth cuticle of the internal root sheath
  • Csft the
  • a follicular unit of scalp hair is typically composed of two to four terminal hair follicles; one, rarely two vellus hair follicles; their associated sebaceous glands, neurovascular plexus, an erector pilorum muscle and a circumferential band of adventitial collagen, termed the "perifolliculum” ( Headington JT, 1984, Arch. Dermatol. 120:449-456 ; Bernstein RM, 2005, "Follicular Unit Hair Transplantation," Ch. 34 in Surgery of the Skin, Robinson et al., eds., St. Louis: Mosby, pp. 549-574 ).
  • Hair follicles are believed to produce approximately 20 individual hair shafts over the life of the follicle as the follicle progresses through cycles of hair production, shedding (ejection), involution and new growth.
  • the regulation of hair growth and follicle regeneration have been investigated in murine systems.
  • the biology of hair follicles in the mouse is different from those of the human in several important aspects.
  • a thick fur coating is essential to healthy life (because hair plays roles in thermoregulation and other functions.)
  • Mouse skin is covered with hair follicles that produce terminal hair (fur), whereas significant regions of human skin are covered with hair follicles that produce vellus hair, which is much less visible or even invisible.
  • Mouse and other non-primate mammals have synchronous Follicle Cycles in early life, although the hair follicle cycles become less synchronous with age. Human follicles progress through the Follicle Cycle in an asynchronous fashion. On an adult human scalp, at any particular time approximately 80-90% are in anagen; 10-20% in telogen and 1-2% in catagen. While the mouse has certain specialized follicles (e.g., whiskers, guard, awl, suchene, and zigzag hair), mouse follicles are generally not subject to developmental and gender-specific hair patterning. In contrast, a significant number of human follicles are individual participants in choreographed hair patterning that affects the type, length and color of shaft produced at different times in development and aging and in a gender specific manner.
  • follicles e.g., whiskers, guard, awl, suchene, and zigzag hair
  • mouse follicles are generally not subject to developmental and gender-specific hair pattern
  • follicle formation occurs but once in a lifetime ( in utero ), so that a mammal, and particularly a human, is born with a fixed number of follicles, which does not normally increase thereafter.
  • follicle neogenesis was not proven because of the lack of tools needed to demonstrate the occurrence or hair follicle neogenesis ( see , Argyris et al., 1959, Dev. Biol. 1: 269-80 ; Miller, 1973, J. Invest. Dermatol. 58:1-9 ; and Kligman, 1959, Ann NY Acad Sci 83: 507-511 ).
  • hair follicle neogenesis can be associated with wound healing in animals (e.g ., rabbits, mice). See, Stenn & Paus, 2001, Physiol. Revs. 81:449-494 . More recently, a series of murine experiments definitively showed that hair follicle-derived epithelial stem cell progenitors migrate out of the follicle and contribute to the re-epithelialization of injured skin ( see , Morris et al., 2004, Nature Biotechnology 22:411-417 ; Ito et al., 2004, Differentiation 72:548-57 ; and Ito et al., 2005, Nature Medicine 11:1351-1354 ).
  • Fathke In animal studies designed to explore the role of Wnt in hair follicle development, Fathke showed that prolonged activation of Wnt signaling during wound healing in mice resulted in generation of rudiments of hair follicles but did not result in the formation of hair follicles or growth of more hair ( Fathke et al., 2006, BMC Cell Biol. 7:4 ).
  • Fathke cutaneous repair in adult mammals following full thickness wounding is understood to result in scar tissue and the loss of the regenerative capability of the hair follicle. Severe wounds and bums are usually associated with a form of cutaneous repair that results in scar tissue and no hair follicles ( see , Fathke et al., 2006, BMC Cell Biol. 7:4 ). However, in a mouse study, Cotsarelis showed that physically disrupting the skin and existing follicles, in a defined fashion, can lead to follicle neogenesis ( Ito et al., 2007, Nature 447:316-321 ).
  • Cotsarelis showed that following closure of large healed wounds created by full thickness excision (FTE) (1 cm 2 square wounds) in mice, new hairs are formed at the center of the wound ( Ito et al., 2007, Nature 447:316-321 ). ( Argyris, 1976, Amer J Pathol 83:329-338 ). In humans, dermabrasion was performed by planing to an approximate depth of 2 mm about halfway through the dermis of the facial skin and the formation of vellus hair follicles was observed ( Kligman, 1956, J Invest Dermatol 27: 19-23 ). These findings have not been translated to clinical regimens for treatment of hair loss.
  • FTE full thickness excision
  • human skin is essentially covered with hair follicles.
  • the portions of human skin where hair is not readily visible contain, for the most part, hair follicles that produce "vellus hair” which is thin and short (i.e., less than 2 mm in length and/or less than 30 microns in diameter), and can have a fine or "fuzzy” appearance, and is often colorless.
  • Certain other hair follicles may contain or produce no hair. Only a minority of human hair follicles produce a hair fiber that can be readily appreciated visibly (a "terminal hair") and these specialized follicles are localized on specific regions of skin.
  • Another follicle type is the "sebaceous" follicle, which is, from its inception, a hair follicle with a very small hair shaft, a very large sebaceous gland, and a large canal and pore.
  • Human fetus follicles may produce lanugo hair during gestation, which is intermediate fine, short, and poorly pigmented and is typically shed by the time of normal birth.
  • lanugo hair can reappear in starvation or in eating disorders such as anorexia nervosa and bulimia and also postnatally in congenital hypertrichosis lanuginosa, and acquired hypertrichosis lanuginosa, in the latter case associated with cancer).
  • Gender is associated with specific patterning of human hair.
  • the growth and loss of visible hair in specific areas of the skin, in stereotypical gender dimorphic patterns, are regarded as “Secondary Sexual Characteristics.”
  • This terminology relates "secondary” features such as hair patterning to the genitals and reproductive organs, which are termed “Primary Sexual Characteristics.”
  • Primary Sexual Characteristics The distinctive genitals and reproductive organs of males and females acquired during embryonic development undergo further changes in puberty and menopause/andropause. In addition to hair growth and loss, breasts in females are also considered Secondary Sexual Characteristics.
  • Certain human hair follicles are targeted to specific skin areas and develop specialized characteristics during embryogenesis under the influence of sex hormones such as testosterone and dihydrotestosterone ("androgens") and/or estrogens. Further, certain human hair follicles are driven to change activity by sex hormones during puberty and in menopause/andropause.
  • the appearance and intensity of secondary sex characteristics can be described as being regulated by ratios of androgens and estrogens, since to a certain extent either of these groups of hormones (androgens and estrogens) can act to induce certain activities or to inhibit the effect of the other group (i.e., androgens inhibit estrogen effects and estrogens inhibit androgen effects).
  • androgens induce male characteristics and suppress female characteristics while estrogens induce female characteristics and suppress male characteristics.
  • Male and female refer to the extremes of genetic gender dimorphism and include by reference the various conditions and states that represent a spectrum of male and female features (such as XO syndromes or conditions that result from exogenous sex steroid administration).
  • Specialized human hair follicles have quantitative variation in activity as well as qualitative variation.
  • sex steroids have qualitative effects on hair patterning either in embryogenesis or in adult life or both (e.g ., males have beard hair follicles that produce terminal hair after puberty whereas females do not).
  • Males and females also vary in the amount of gender-specific hair patterning (e.g. , a higher density of leg hair follicles produce terminal hair on male rather than female legs).
  • individuals of the same gender exhibit quantitative variation. For example, male chest and back hair presents in different individuals as a spectrum from almost hairless to dense hair and from small regions of follicles producing terminal hair to large regions.
  • Gender specific human hair patterning highlights the distinct biological programming of specific hair follicles. Distinct hair follicles in relative proximity on the male scalp and face respond to high androgen/estrogen ratios in diametrically opposite ways: high androgen/estrogen ratios induce vellus to terminal hair transformation in male moustache/beard skin (particularly during puberty), but induce terminal to vellus follicle transformation change in male frontal/temporal scalp (progressively post puberty) in male pattern hair loss.
  • Hair follicles in the axillary and pubic regions appear to be more sensitive to androgen than moustache/beard follicles; since terminal hair in axillae/pubis grows: (a) in females with relatively low levels of androgen; (b) early in male puberty before beard/moustache; and (c) in patients with genetic 5-alpha-Reductase Type II deficiency.
  • Androgenetic alopecia is a genetically-mediated disorder that occurs in approximately 50% of men by the age of 50 years (see review, Stough et al, 2005). In women, the histological features of the condition are the same as in men, but susceptibility, age at onset, rate of progression and pattern of hair loss differ between genders (Dinh and Sinclair, 2007).
  • the loss of scalp hair in men is known to be a process driven by the androgen dihydrotestosterone (DHT), which can be inhibited and to some extent reversed by finasteride, which inhibits 5-alpha-reductase II (which converts testosterone to DHT).
  • DHT dihydrotestosterone
  • finasteride which inhibits 5-alpha-reductase II (which converts testosterone to DHT).
  • DHT dihydrotestosterone
  • finasteride which inhibits 5-alpha-reductase II (which converts testosterone to DHT).
  • 5-alpha-reductase II which converts testosterone to DHT
  • senescent involuted irreparably
  • Telogen hairs are more loosely anchored and prone to shedding or being pulled out (for example, by combing or brushing hair).
  • a club hair is produced that is a fully keratinized hair.
  • the hair follicles on MPHL affected areas also undergo follicular miniaturization in which a growing proportion of terminal follicles become vellus follicles.
  • androgenetic alopecia is thought to involve the progressive conversion of hair follicle units with 3 or more terminal hairs to follicular units having fewer terminal hairs (e.g., units with 2 terminal hairs progress to units with 1 terminal hair).
  • Thinning of the hair can also occur in older individuals when amounts of testosterone and DHT in the body are decreasing. This can either be an extension of MPHL from the earlier years or even start in the latter decades of life (i.e. age-related hair thinning).
  • MPHL is associated with specific polymorphisms of the androgen receptor, the EDA2R gene. Men who are genetically deficient in Type II 5-alpha-reductase do not experience MPHL ( see Jenkins et al., 1992, J Clin Invest 89:293-300 ).
  • Hic-5/ARA55 mRNA expression was high in dermal papilla cells from the beard and bald frontal scalp but low in cells from the occipital scalp.
  • ARA70/ELE1 Another androgen receptor coactivator ARA70/ELE1 had decreased expression of a splice variant form (ARA70beta/ELE1beta) in the dermal papilla of balding recipient areas than non-balding areas ( Lee et al., 2005, J Cutan Pathol 32:567-571 ). There is evidence that there is increased methylation of the Hic-5/ARA55 gene in occipital hair follicles which may "protect" these hair follicles from androgen mediated hair loss. See Cobb et al. Br J Dermatol. 2011;165(1):210-213 .
  • FPHL is thought to share some features with MPHL in terms of progressive reduction in the duration of anagen and progressive follicular miniaturization, although recent studies have found a prolongation of kenogen.
  • MPHL thinning of the hair, especially on the top of head, in addition to affecting younger individuals, can also occur in older individuals when amounts of testosterone and DHT in the body are decreasing This can either be an extension of FPHL from the earlier years or even start in the latter decades of life (i.e. age-related hair thinning).
  • Scarring alopecia also known as cicatricial alopecia, includes primary cicatricial alopecia (PCA) and secondary cicatricial alopecia.
  • PCA primary cicatricial alopecia
  • Secondary cicatricial alopecia describes a rare group of diverse hair disorders that cause permanent destruction and scarring of the hair follicle in otherwise healthy men and women of all ages (http://www.carfintl.org/faq.html; Price VH, 2006, "The medical treatment of cicatricial alopecia," Semin Cutan Med Surg 25:56-9 ).
  • the hair follicle is the primary target of a folliculocentric inflammatory attack that results in destruction and replacement of the sebaceous gland and follicular stem cells with fibrous (scar) tissue.
  • Secondary cicatricial alopecia describes an incidental destruction of the follicular unit following severe infections, tumors, burns, or radiation.
  • Primary cicatricial alopecia represents at least eight rare diseases that cause permanent hair loss. The clinical course of these diseases is highly variable and unpredictable. Hair loss may slowly progress over many years, or may occur rapidly within months. Itching, pain and burning are often severe and incapacitating.
  • Primary cicatricial alopecia is currently classified by the histopathological analysis of scalp biopsies, which stratifies those with a predominantly lymphocytic inflammation from those with a predominantly neutrophilic inflammation, and from those with a mixed infiltrate.
  • Lymphocyte-mediated PCA includes lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA), and pseudopelade (Brocq).
  • Neutrophil-mediated PCA includes folliculitis decalvans and tufted folliculitis.
  • a mixed inflammatory infiltrate occurs in dissecting cellulitis and folliculitis keloidalis, both of which are secondary to follicular rupture.
  • transplanted follicles retain the programmed terminal hair producing features from their original location.
  • recipient site may affect some characteristics of transplanted hairs. S ee Hwang et al., 2002, Dermatol. Surg. 28:795-799 .
  • Human hair loss can be categorized as (1) gender specific hair patterning, (2) pathological hair loss, or (3) hair loss after wounding, all which can be associated with effects on self-esteem and self-image, and many individuals explore whether their hair loss process can be treated.
  • Current treatments offered involve a limited selection of agents and regimens, such as chemical and surgical approaches that either stimulate or transplant pre-existing hair.
  • Minoxidil and antiandrogens are reasonably effective in stimulating the growth of vellus and miniaturized hair in certain MPHL conditions. While these types of treatments are reasonably effective in delaying MPHL, they are less effective in both preventing MPHL and stimulating the growth of significant terminal hair in scalp of MPHL after baldness has advanced, consistent with some kind of terminal senescence or involution of the follicle. Even when effective, these drugs do no create hair follicles of the kind that were there before balding, and the resultant hair follicles are smaller and the scalp has less density of terminal hairs.
  • minoxidil trade name Rogaine
  • antiandrogens such as finasteride (trade names Propecia, Proscar), dutasteride or ketoconazole.
  • Minoxidil and antiandrogens are reasonably effective in stimulating the growth of vellus and miniaturized hair in certain MPHL conditions. While these types of treatments are reasonably effective in delaying MPHL, they are less effective in both preventing MPHL and stimulating the growth of significant terminal hair
  • minoxidil and finasteride are effective only for as long as it is taken; the hair gained or maintained is lost within 6-12 months of ceasing therapy. See, e.g., Rossi, ed., 2004, Australian Medicines Handbook. Sydney: Australian Medicines Handbook .
  • minoxidil and finasteride require continuous treatment for lasting effects.
  • patients with advanced MPHL may express dissatisfaction with even statistically significant, but cosmetically insignificant increase in hair counts and such frustration may contribute to poor compliance and further unsatisfactory outcomes.
  • bimatoprost a prostaglandin analog used to control the progression of glaucoma in the management of ocular hypertension
  • Latisse® a prostaglandin analog used to control the progression of glaucoma in the management of ocular hypertension
  • Finasteride is not approved for females, while minoxidil is FDA approved for both males and females.
  • Kopexil e.g., Keranique
  • minoxidil is a modified form of minoxidil that has been proposed to have fewer side effects, and therefore has been proposed for treatment of hair loss in females.
  • patient dissatisfaction with statistically significant, but cosmetically insignificant increase in hair counts contribute to poor compliance and unsatisfactory outcomes.
  • Minoxidil use is further complicated by the fact that it is messy and can leave a residue.
  • many patients are dissatisfied with the side effects from persistent finasteride or minoxidil treatment, such as sexual dysfunction in the case of the 5-alpha-reductase inhibitors.
  • a device that uses low level light energy directly on the scalp has received FDA clearance as a 510K device. Although the device is advertised as a "Laser,” it operates by applying low level monochromatic light energy directly to the scalp, which is thought to stimulate hair growth through "photo-biostimulation" of hair follicles.
  • Various types of devices operating on similar principles were referenced as the predicate for HairMax ( see , Lolis et al., 2006, J. Cosmetic Dermatol. 5:274-276 ).
  • hair transplantation-in which scalp strips, hair follicles or follicular units from the occipital scalp (which are resistant to the effects of androgens in inducing AGA-type alopecia) are excised and transplanted to a person's balding or thinning areas.
  • Another surgical method that has been used is scalp reduction; in this procedure, the skin in the balding area of the scalp is surgically excised and the surrounding skin (with hair) is pulled together and sutured.
  • Surgical methods are best for focal hair loss, and are less effective for diffuse hair loss, are less effective for women, and younger patients are not ideal candidates because the pattern and extent of future hair loss is variable.
  • hair transplantation can be inconvenient because of the invasive nature of the surgery, recovery time, duration of time to show a cosmetic effect (around 6-12 months), creation of scarring, and expense.
  • cosmetic coverage is constrained by the area of and the number of hairs in a patient's donor sites.
  • PCA Primary cicatricial alopecia
  • Patients with lymphocytic PCA are typically prescribed oral, topical or intralesional injections of anti-inflammatory drugs.
  • Oral drugs include hydroxychloroquine, doxycycline, mycophenolate mofetil, cyclosporine, or corticosteroids; topical drugs include corticosteroids, topical tacrolimus, or topical pimecrolimus; and triamcinolone acetonide is used as an injected drug.
  • Antimicrobial drugs are prescribed for neutrophilic (neutrophil-mediated) PCA after culture and sensitivities direct the appropriate selection. Dissecting cellulitis, with its mixed infiltrate, responds to isotretinoin treatment.
  • Integumental perturbation is used to promote the growth of hair in a subject, in particular, a human subject.
  • devices and methods for using integumental perturbation to promote the growth of hair results in an increase in the amount or thickness of hair on an area of skin of a subject.
  • a method provided herein for using integumental perturbation to promote the growth of hair results in an increase of vellus hair on an area of skin of a subject.
  • the methods of integumental perturbation provided herein are accompanied by administration of a non-occlusive, topical pharmaceutical composition.
  • the methods of integumental perturbation are accompanied by administration of a pharmaceutical composition comprising a hair growth-promoting agent.
  • the methods of integumental perturbation are accompanied by administration of a pharmaceutical composition comprising an agent that promotes the transition of vellus hair to terminal hair.
  • integumental perturbation accompanied by ( i.e ., before, during, and/or after) administration of one or more hair growth-promoting agents, which may be, in a particular aspect, an agent that promotes the transition of vellus hair to terminal hair or the transition of resting or telogen hair follicles into growing or anagen hair follicles.
  • a method provided herein for using integumental perturbation in combination with one or more hair growth-promoting agents to promote the growth of hair results in an increase in terminal hair on an area of skin of a subject
  • a method is provided herein comprising using integumental perturbation to promote the transition of the number of vellus hairs to terminal hairs followed by administration of one or more hair growth-promoting agents to sustain and/or further increase the size of these new terminal hairs from the perturbation, which otherwise would revert back to vellus-sized hairs.
  • a method comprising using integumental perturbation to increase the number of new terminal hairs followed by administration of one or more hair growth-promoting agents to sustain and/or further increase the size of these new terminal hairs from the perturbation, which otherwise decrease in size and become vellus-sized hairs.
  • a method is provided herein for using integumental perturbation in combination with one or more hair growth-promoting agents to promote the growth of hair results in an increase in the amount or thickness of hair on an area of skin of a subject.
  • integumental perturbation refers to any treatment of the skin and/or other tissues of the integumentary system that results in debriding, peeling, or wounding, or other perturbation of the skin.
  • the procedure can be controlled to limit perturbation to part or all of the epidermis, to part or all of the stratum corneum, or deeper into the papillary dermis, reticular dermis, and/or hypodermis.
  • the epidermis is removed and, e.g ., the papillary dermis is disrupted.
  • the occurrence of pinpoint bleeding would indicate removal of the stratum corneum, epidermis (or part thereof) and portions of the upper layer of the dermis, such as the superficial papillary dermis.
  • the occurrence of increased bleeding would indicate deeper penetration (and thus perturbation) into the deeper papillary dermis and reticular dermis layer.
  • the integumental perturbation method causes only superficial wounding to the area of skin on which hair growth is desired.
  • the extent of wounding is minimized by controlling the depth of perturbation.
  • the extent of wounding is minimized by controlling the size of the perturbed area of skin; for example, by making a series of small wounds to effect wounding of a large area rather than a single large wound.
  • removal of the epidermis can be detected by the appearance of a shiny, whitish, and smooth layer of skin.
  • the disruption of the superficial papillary dermis can be detected, e.g., by the appearance of small pinpoints of blood over a shiny, whitish, smooth surface in the treated area. Perturbing to the deeper papillary dermis results in more bleeding and the treated surface appears rougher. After entering the reticular dermis, bleeding becomes confluent and brisk, the surface appearance is rougher than the deep papillary dermis, representing exposed dermal collagen.
  • integumental perturbation results in partial removal of the epithelium. In other embodiments, integumental perturbation results in complete removal of the epithelium but does not go deeper into the dermis.
  • a method of integumental perturbation described herein disrupts skin to a depth of between 30 ⁇ m to 200 ⁇ m ( e.g., to a maximum depth of 30, 40, 50, 60, 70, 80, 85, 90, 95, 100, 105, 110, 120, 130, 140, 150,160,170, 180, 190 or 200 ⁇ m), and preferably to approximately 100-150 ⁇ m.
  • a method of integumental perturbation described herein disrupts skin to a depth of 100 ⁇ m.
  • a method of integumental perturbation described herein disrupts skin to a depth of 150 ⁇ m.
  • integumental perturbation is accomplished using chemical treatments (e.g ., an inflammatory agent, caustic agent, etc.), or mechanical or electromagnetic or physical treatments including but not limited to dermabrasion (DA), particle-mediated dermabrasion (PMDA), microdermabrasion, microneedles, laser (e.g., a laser that delivers ablative, non-ablative, fractional, non-fractional, superficial, or deep treatment, and/or that is CO 2 -based, or erbium-YAG-based, erbium-glass based (e.g.
  • neodymium:yttrium aluminum garnet (Nd:YAG) laser etc .
  • a low-level (low-intensity) laser therapy treatment e.g ., HairMax Laser comb
  • laser abrasion e.g., irradiation, radio frequency (RF) ablation
  • dermatome planing e.g.
  • dermaplaing a coring needle, a puncture device, a punch tool or other surgical tool, suction tool or instrument, electrology, electromagnetic disruption, electroporation, sonoporation, low voltage electric current, intense pulsed light, or surgical treatments (e.g ., skin graft, hair transplantation, strip harvesting, scalp reduction, hair transplant, follicular unit extraction (FUE), robotic FUE, etc .), or supersonically accelerated saline (jetpeel; Golan et al., Ann Plast Surg. 2005;54(4):369-374 .) that promote the growth of hair.
  • Methods and devices for integumental perturbation in accordance with this aspect are described in Section 5.1 infra.
  • the invention excludes freezing or chemically treating the area of skin to be integumentally perturbed.
  • integumental perturbation is performed using a diamond fraize.
  • integumental perturbation is performed at a depth that results in the histological presence of the PEL and PELA structures.
  • integumental perturbation is performed on a transitional area of the scalp in subjects with AGA-type alopecia.
  • integumental perturbation is performed on subjects with Fitzpatric skin types 1-4.
  • a dermabrasion tip for use on a dermabrasion hand piece that addresses the above-discussed drawbacks with conventional dermabrasion devices.
  • a dermabrasion tip for use on a dermabrasion hand piece comprises:
  • a dermabrasion tip for use on a dermabrasion hand piece comprises:
  • a dermabrasion tip for use on a dermabrasion hand piece comprises:
  • a dermabrasion tip for use on a dermabrasion hand piece comprises:
  • a dermabrader comprises:
  • a kit for dermabrasion comprises:
  • kits for dermabrasion comprises:
  • integumental perturbation for promoting hair growth on an area of skin of a subject, wherein the integumental perturbation comprises dermabrasion.
  • dermabrasion is accomplished using the dermabrasion tip, dermabrader, and/or kit for dermabrasion described in Section 5.1 infra.
  • dermabrasion is performed using a diamond fraize.
  • Objects of the invention are to promote generation of new hair follicles ("follicle neogenesis"); to promote formation of neogenic-like (NL) follicular structures; to promote activation (possibly by reorganization) of existing hair follicles; to promote formation of pre-existing-like (PEL) or pre-existing-like, attached (PELA) follicular structures; to promote development of hair follicles, for example, to promote the growth of terminal hair (in preference to vellus hair); to promote the branching of pre-existing hair follicles (seen as an increased number of hair shafts per pore); to increase the width of hair follicles (thereby promoting growth of an increased shaft width); and/or to delay or prevent follicle senescence.
  • follicle neogenesis new hair follicles
  • NL neogenic-like
  • PELA pre-existing-like, attached
  • Further objects of the invention are to promote the growth of hair; to promote growth of vellus hair; to promote the transition of vellus hair to terminal hair; to increase the amount of hair follicles in anagen, to prolong anagen, to shorten telogen, to promote growth of terminal hair; to increase the amount of hair; to increase the thickness of hair; and/or to reduce or prevent hair loss.
  • Additional objects of the invention are to promote activation, reorganization, or regeneration of hair follicle units or generation of new hair follicle units; to promote development of hair units, for example, to promote the growth of terminal hair (in preference to vellus hair) for or in follicular units; to promote the branching of pre-existing hair follicle units (seen as an increased number of hair shafts per pore); to increase the width of hair in hair follicle units (thereby promoting growth of increased shaft widths); and/or to delay or prevent follicle unit senescence.
  • Further objects of the invention are to promote the growth of hair in follicular units; to promote growth of vellus hair in follicular units, to promote the transition of vellus hair in follicular units to terminal hair in follicular units; to promote growth of terminal hair in follicular units; to increase the amount of hair in follicular units; to increase the thickness of hair in follicular units; and/or to reduce or prevent hair loss or hair miniaturization in follicular units.
  • the treatments described herein may achieve these results by increasing the capacity of the skin to generate new hair follicles and/or new follicle units; increasing the capacity of the skin to reprogram hair follicle and/or hair follicle unit development; increasing the capacity of the skin to reorganize and activate existing hair follicles and follicular structures; regulating the unique human processes that regulate visible hair growth; regulating the activity of specialized human hair follicles and/or hair follicle units; regulating specific activities of specialized human hair follicles and/or hair follicle units; regulating gender-specific specialized human hair follicles and/or hair follicle units, including those under the influence of sex-steroid regulation; altering the activity of specialized human hair follicles and/or hair follicle units, sometimes in conjunction with transplantation; regulating the differentiation of stem cells into gender-specific specialized human hair follicles and/or hair follicle units, that may
  • the invention is based, in part, on the principle that human skin is replenished by stem cells, such as bone-marrow derived and tissue-derived stem cells, throughout life.
  • stem cells such as bone-marrow derived and tissue-derived stem cells
  • Follicle Stem Cells can be derived from (1) other Follicle Stem Cells, (2) from other tissue stem cells, termed "pre-Follicle Stem Cells" (from the interfollicular skin), (3) from bone marrow-derived stem cells (“BMST”), and/or (4) from mesenchymal stem cells such as adipocyte stem cells.
  • BMST bone marrow derived stem cells
  • their differentiation into Follicle Stem Cells requires intact follicles, whose cells can play the role of "nurse cells” and provide appropriate signals to guide the differentiation of bone marrow derived stem cells into Follicle Stem Cells.
  • Integumental perturbation (1) provides signals for Follicle Stem Cells to divide symmetrically to begin the process of forming new follicles; (2) mobilizes tissue stem cells ("pre-Follicle Stem Cells") from interfollicular skin to differentiate into stem cells, (3) increases the trafficking of bone marrow derived stem cells to affected areas of skin and promotes their differentiation into Follicle Stem Cells by nurse cells in existing follicles, and (4) encourages the "mixing" of hair follicles, hair follicle precursor cells, and other types of inductive cells, which may enable signals from precursor cells to induce hair follicle activation and development.
  • a method described herein comprises contacting a precursor cell with an inductive cell.
  • the invention is based in part on the discovery that, while hair growth can be promoted by true hair follicle neogenesis, other follicular structures that need not arise from de novo formation of neofollicles can be stimulated, activated and reorganized in order to promote hair growth. Many conventional pharmacologic treatments for hair growth promotion encourage the switch from vellus to terminal hair.
  • the integumental perturbation methods described herein promote the formation of stimulated, activated and reorganized hair follicle structures which correlate with increased vellus hair, if not terminal hair.
  • a combination of integumental perturbation and one or more pharmacologic treatments results in increased hair, increased hair thickness, and/or longer lasting hair.
  • such a combination treatment results in a 1.25-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, or 4-fold or more increase in the amount of hair compared to treatment with a pharmacologic treatment alone.
  • the present invention can exclude the administration of other therapeutic agents, for example, hair growth-promoting agents.
  • the present invention comprises serial perturbations in the same treated area, either with or without pharmaceutical agents, to produce an additive hair growth effect.
  • the present invention comprises one or more perturbations in the same treated area, either with or without one or more pharmaceutical agents, to produce a synergistic effect, i.e ., to grow more hair than would be expected of the additive effect of either of the treatments alone.
  • the present invention comprises integumental perturbation in combination with one or more additional therapeutic agents.
  • the present invention comprises integumental perturbation in combination with an additional treatment, wherein the additional treatment may or may not include an active pharmaceutical ingredient (see, e.g., Section 5.2 infra ).
  • the additional treatment comprises an active pharmaceutical ingredient or active pharmaceutical ingredients for promoting the growth of hair, including vellus hair or terminal hair, preventing infection, and/or promoting healing of perturbed skin. Methods and pharmaceutical compositions for use in accordance with this aspect are described in Sections 5.2, 5.3, and 5.4 infra.
  • an integumental perturbation method of the invention is used in combination with other agents or treatments that stimulate hair growth.
  • an integumental perturbation method of the invention can be administered before, concurrently, after, or alternating with one or more hair growth-promoting agents.
  • Hair growth-promoting agents for use, alone or in combination, in accordance with this aspect include but are not limited to: agents affecting prostaglandins, such as Prostaglandin F2 ⁇ analogs, e.g.
  • latanoprost (trade name Xalatan), travoprost (trade name Travatan), tafluprost, unoprostone, dinoprost (trade name Prostin F2 Alpha), AS604872, BOL303259X, PF3187207, carboprost (trade name Hemabate); Prostamides, e.g., bimatoprost (trade names Latisse, Lumigan); Prostanoid receptor agonists, e.g. fluprostenol; Prostaglandin D2 receptor antagonists, e.g. laropiprant, AM211; Prostglandin E2 analogs, e.g.
  • sulprostone e.g. butaprost
  • EP 2 receptor agonists e.g. butaprost
  • 5 ⁇ -reductase inhibitors such as, e.g., finasteride, dutasteride, turosteride, bexlosteride, izonsteride, epristeride, epigallocatechin, Fluridil ( Sovak et al, Dermatol Surg. 2002;28(8):678-685 ), RU 58841 ( Pan et al. Endocrine.
  • kopexil for example, the product KeraniqueTM
  • CaCl 2 botilinum toxin A, adenosine, ketoconazole, DoxoRx, Docetaxel, FK506, GP11046, GP11511, LGD 1331, ICX-TRC, MTS-01, NEOSH101, HYG-102440, HYG-410, HYG-420, HYG-430, HYG-440, spironolactone, CB-03-01, RK-023, Abatacept, Viviscal®, MorrF, ASC-J9, NP-619, AS101, Metron-F-1, PSK 3841, Targretin (e.g., 1% gel), MedinGel, PF3187207, BOL303259X, AS604872, THG11331, PF-
  • kopexil for example, the product KeraniqueTM
  • CaCl 2 botilinum toxin A, aden
  • hair-growth promoting agents include arginine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, gamma linoleic acid and polyphenol catechins, copper peptides.
  • Other hair-growth promoting agents that can be formulated as a hair wash tonic could include but are not limited to, jojoba oil, extract of apple, saw palmetto, emu oil, beta carotene and green tea.
  • an integumental perturbation method of the invention is used in combination with drugs for alopecia being developed by SWITCH Biotech LLC.
  • one or more of the foregoing may be used in its commercially available form.
  • the dosage of one or more of the foregoing is adjusted to optimize a combination treatment (e.g ., integumental perturbation or treatment with another active ingredient or active ingredients) described herein.
  • the formulation of one or more of the foregoing is adjusted to optimize a combination treatment (e.g ., integumental perturbation or treatment with another active ingredient or active ingredients) described herein.
  • one or more of the foregoing is formulated for topical administration, e.g., by incorporation into a pharmaceutical composition for post-perturbation treatment described in Section 5.2 infra.
  • the hair growth-promoting agent used in accordance with this aspect enhances conversion of vellus hair to nonvellus hair.
  • the hair growth-promoting agent enhances conversion of vellus hair to terminal hair.
  • Exemplary hair growth-promoting agents that promote conversion of vellus to nonvellus or terminal hair that may be used in accordance with this aspect are prostaglandin F2 ⁇ analogs (in one aspect, latanoprost), prostamides (in one aspect, e.g., bimatoprost), minoxidil, etc.
  • minoxidil is administered in combination with a prostaglandin F2 ⁇ analog.
  • minoxidil is administered in combination with a prostamide.
  • minoxidil is administered in combination with a 5 ⁇ -reductase inhibitor. In one such embodiment, minoxidil is administered in combination with finasteride.
  • Methods and pharmaceutical compositions comprising "hair growth-promoting agents" for use in accordance with this aspect are described in Section 5.3 infra.
  • a method comprising using integumental perturbation to promote the transition of the number of vellus hairs to terminal hairs followed by administration of a hair growth-promoting agent to sustain and/or further increase the size of these new terminal hairs from the perturbation, which otherwise would revert back to vellus-sized hairs.
  • a method is provided herein comprising using integumental perturbation to increase the number of new terminal hairs followed by administration of a hair growth-promoting agent to sustain and/or further increase the size of these new terminal hairs from the perturbation, which otherwise decrease in size and become vellus-sized hairs.
  • a method provided herein for using integumental perturbation in combination with a hair growth-promoting agent to promote the growth of hair results in an increase in the amount or thickness of hair on an area of skin of a subject.
  • the invention provides a method for promoting hair growth on the scalp of a male or a female subject with androgenetic alopecia wherein the method comprises in the following order: (i) applying integumental perturbation; (ii) optionally applying a non-occlusive wound dressing to the integumentally perturbed skin area; and (iii) administering minoxidil topically.
  • integumental perturbation is performed using dermabrasion with an estimated depth of 100-150 microns, a hydrogel is administered to the skin, and minoxidil is administered in the form of 5% minoxidil foam.
  • Minoxidil can be administered as a liquid, gel, and/or foam at a concentration of 2-5% Minoxidil..
  • the hydrogel is administered topically immediately following dermabrasion twice daily for about 1 week, followed by a 3 week period without treatment, which in turn is followed by a period of at least 5 months of minoxidil treatment.
  • the hydrogel is administered topically immediately following dermabrasion twice daily for 12 days, which in turn is followed by a period of 6 months of minoxidil treatment.
  • the treatment regimen is repeated multiple times to build up hair density over time.
  • the invention provides a method for inducing hair growth on the scalp of a male or female subject with androgenetic alopecia, wherein the method comprises:
  • the invention provides a treatment regimen that starts minoxidil as soon as re-epithelialization is complete. In one embodiment, re-epithelialization is complete between 11 days and 14 days after post integumental perturbation.
  • a drug spraying device disclosed herein comprises a drug cartridge having two separate chambers that keep drug components isolated until the therapeutic compound is to be dispensed.
  • a drug spraying device disclosed herein enables the sustained release of a hair growth-promoting agent, without the use of highly hydrophobic, occlusive matrices.
  • a drug spraying device disclosed herein enables the sustained release of a hair growth-promoting agent and uptake by the skin through a scab.
  • a drug spraying device disclosed herein enables the concurrent delivery of two or more drugs.
  • a drug spraying device disclosed herein enables the cleansing of the integumentally perturbed skin and administration of one or more drugs with one single device.
  • Exemplary devices and their use with exemplary pharmaceutical compositions for the practice of this aspect of the invention are described in Section 5.5.2.1 infra.
  • the methods described herein are used to replenish hair in scalp that was used or could be used as a donor site for hair transplant surgery.
  • Success of a method of the invention can be measured by, for example:
  • Human subjects who are candidates for the treatments disclosed herein include any subject for whom increased hair growth is desired including, but not limited to, subjects with nonscarring (noncicatricial) alopecia, such as androgenetic alopecia (AGA), including male pattern hair loss (MPHL) or female pattern hair loss (FPHL), age-related hair loss (senescence), or any other form of hair loss caused by androgens, toxic alopecia, alopecia areata (including alopecia universalis), scarring (cicatricial) alopecia, pathologic alopecia (caused by, e.g., medication, chemotherapy, trauma, wounds, burns, stress, autoimmune diseases), trichotillomania, malnutrition, or endocrine dysfunction), or hypotrichosis, or any other disease, disorder, or form of hair loss as discussed infra and/or known in the art.
  • nonscarring nonscarring
  • AGA androgenetic alopecia
  • MPHL male pattern hair loss
  • a human subject who is a candidate for such treatments is a human subject with scarring (cicatricial) alopecia.
  • cicatricial alopecia forms of cicatricial alopecia that may be treated in accordance with the methods described herein include primary cicatricial alopecia (PCA) and secondary cicatricial alopecia.
  • Primary cicatricial alopecias that may be treated in accordance with the methods described herein include lymphocyte-mediated PCAs, such as lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA), and pseudopelade (Brocq); neutrophil-mediated PCAs, such as folliculitis decalvans and tufted folliculitis; and PCAs involving a mixed inflammatory infiltrate, such as occurs in dissecting cellulitis and folliculitis keloidalis.
  • lymphocyte-mediated PCAs such as lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA), and pseudopelade (Brocq)
  • neutrophil-mediated PCAs such as folliculitis decalvans and tufted folliculitis
  • a method for enhancing hair growth in a patient with scarring alopecia comprising controlled integumental perturbation using dermabrasion, followed by twice daily topical administration of a hydrogel for 7-14 days, preferably 12 days, followed by administration of one or more hair growth promoting agents.
  • the hydrogel treatment is begun on the same day as the laser treatment.
  • the patient has primary scarring alopecia.
  • the patient has lichen planopilaris.
  • the patient has frontal fibrosing alopecia.
  • Success of a treatment for scarring alopecia may be measured using the methods described above.
  • successful treatment is determined as an increase in the number of visually or photographically detected hairs.
  • successful treatment is evaluated by a skin biopsy for hair follicle structures and scar attributes. Success may also be measured as a reduction or elimination of itching, burning, pain, and tenderness associated with the condition, or a reduction of scalp redness, scaling, and/or pustules. Success may also be measured as a reduction or elimination of inflammation of the scalp.
  • a subject e.g ., a human subject
  • methods of treating baldness or alopecia in a subject comprising subjecting an affected area of the skin to integumental perturbation.
  • methods of enhancing, stimulating, or increasing hair growth or enhancing or increasing the thickness of hair in some embodiments collectively referred to herein as "promoting" hair growth or hair thickness) on an area of skin of a subject (e.g ., a human), the methods comprising subjecting an affected area of the skin to integumental perturbation.
  • the method of treating baldness or alopecia or promoting hair growth or thickness of hair results in formation of new hair follicles ("hair follicle neogenesis"), the formation of neogenic-like hair follicles, activation of existing hair follicles, reorganization of existing hair follicles, an increase in the numbers of vellus hairs, an increase in the numbers of nonvellus hairs (e.g., intermediate or terminal), and/or an increase in the numbers of terminal hairs in the treated area.
  • hair follicle neogenesis new hair follicles
  • the integumental perturbation step is carried out in combination with a second treatment step, the second treatment step referred to herein as a "post-perturbation treatment.”
  • the integumental perturbation step alone or in combination with a post-perturbation treatment step, is carried out in combination with a step comprising treatment with one or more hair growth-promoting agents.
  • methods and devices for integumental perturbation which may be used, inter alia , to promote the growth of hair.
  • pharmaceutical compositions for use in the post-perturbation step and pharmaceutical compositions for use in the hair growth-promoting agent treatment step.
  • a method of integumental perturbation provided herein promotes growth of hair on an area of skin of a subject. In some embodiments, a method of integumental perturbation provided herein increases the amount or thickness of hair on a treated area of skin of a subject. In some embodiments, a method of integumental perturbation provided herein results in an increase in the amount of vellus hair on a treated area of skin of a subject. In some embodiments, a method of integumental perturbation provided herein results in an increase in the amount of terminal hair on a treated area of skin of a subject.
  • a method of integumental perturbation provided herein results in formation of new hair follicles ("hair follicle neogenesis") in a treated area of skin of a subject.
  • a method of integumental perturbation provided herein results in an increased number of hair follicles in a treated area of skin of a subject.
  • the method of integumental perturbation results in formation of new hair follicles with vellus-sized hair shafts (i.e., hair shafts with diameters less than 30 microns in diameter) in a treated area of skin of a subject.
  • a method of integumental perturbation results in an increased number of stimulated and activated hair follicles, such as pre-existing hair follicles, in a treated area of skin of a subject.
  • the method of integumental perturbation results in an increased number of pre-existing hair follicles with vellus-sized hair shafts in a treated area of skin of a subject.
  • the method of integumental perturbation results in the presence and/or increased numbers of NL, PEL, and PELA follicular structures.
  • a method of integumental perturbation described herein comprises dermabrasion, using, e.g., a device described herein.
  • a method of integumental perturbation comprises treatment with laser.
  • Various methods of integumental perturbation are described in Section 5.1 infra , however, the invention is not to be so limited, and any method of integumental perturbation may be used in accordance with the methods described herein.
  • post-perturbation treatments are provided herein.
  • the post-perturbation treatment promotes healing with no or reduced scarring.
  • the post-perturbation treatment is a topical treatment.
  • Pharmaceutical compositions for use in post-perturbation treatment methods are also provided herein.
  • the post-perturbation treatment step comprises topical administration of a pharmaceutical composition that is intended to promote the growth of hair, including vellus hair, terminal hair, increase hair thickness, prevent infection and/or promote healing, e.g., scarless healing, of the perturbed skin.
  • a pharmaceutical composition for use in the post-perturbation treatment step is formulated for topical administration.
  • the pharmaceutical composition formulated for topical administration is non-occlusive.
  • the non-occlusive pharmaceutical composition formulated for topical administration is an aqueous formulation (e.g ., hydrogel), a non-aqueous formulation, an ointment, a suspension, or a cream ( e.g ., emulsion).
  • the pharmaceutical composition formulated for post-perturbation topical administration does not contain an active pharmaceutical ingredient (API).
  • a post-perturbation topical treatment comprises a wound healing gel that does not contain an API.
  • the wound healing gel is applied immediately after integumental perturbation and every day for about a week.
  • the pharmaceutical composition formulated for post-perturbation topical administration contains an active pharmaceutical ingredient or pharmaceutical ingredients, which can be any agent described herein ( e.g ., in Section 5.3 or 5.4) or otherwise known in the art.
  • a post-perturbation treatment is administered immediately after integumental perturbation. In some embodiments, a post-perturbation treatment is administered a certain period of time after integumental perturbation. Although referred to herein as "post-perturbation" treatments, the post-perturbation treatment methods described herein are not by definition limited to treatment steps after integumental perturbation. In some embodiments, a post-perturbation treatment is administered before or during integumental perturbation. In particular embodiments, a post-perturbation treatment is present at more than one time period before, during, and/or after integumental perturbation.
  • a method of integumental perturbation in combination with a post-perturbation treatment provided herein promotes growth of hair on an area of skin of a subject. In some embodiments, a method of integumental perturbation in combination with a post-perturbation treatment provided herein increases the amount or thickness of hair on a treated area of skin of a subject. In some embodiments, a method of integumental perturbation in combination with a post-perturbation treatment provided herein results in an increase in the amount of vellus hair on a treated area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment provided herein results in an increase in the amount of terminal hair on a treated area of skin of a subject. In some embodiments, a method of integumental perturbation in combination with a post-perturbation treatment provided herein results in hair follicle neogenesis in a treated area of skin of a subject. In certain embodiments, a method of integumental perturbation in combination with a post-perturbation treatment provided herein results in an increased number of hair follicles in a treated area of skin of a subject.
  • the method of integumental perturbation in combination with post-perturbation treatment results in formation of new hair follicles with vellus-sized hair shafts (i.e., hair shafts with diameters less than 30 microns in diameter) in a treated area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment provided herein results in an increased number of stimulated or activated hair follicles, such as pre-existing hair follicles, in a treated area of skin of a subject.
  • the method of integumental perturbation in combination with post-perturbation treatment results in an increased number of pre-existing hair follicles with vellus-sized hair shafts in a treated area of skin of a subject.
  • the method of integumental perturbation in combination with post-perturbation treatment results in the presence and/or increased numbers of NL, PEL, and PELA follicular structures.
  • a method of integumental perturbation in combination with a post-perturbation treatment provided herein prevents infection of a treated area of skin. In some embodiments, a method of integumental perturbation in combination with a post-perturbation treatment provided herein promotes healing of perturbed skin. In some embodiments, a method of integumental perturbation in combination with a post-perturbation treatment provided herein promotes healing of perturbed skin with no or reduced scarring.
  • Also provided herein are methods of treating baldness or alopecia in a subject e.g., a human subject
  • the methods comprising (i) subjecting an affected area of the skin to integumental perturbation, optionally carried out in combination with a post-perturbation treatment step, (ii) in combination with a step comprising treatment with one or more hair growth-promoting agents.
  • methods of promoting hair growth or hair thickness on an area of skin of a subject e.g.
  • a human the methods comprising (i) subjecting an affected area of the skin to integumental perturbation, optionally carried out in combination with a post-perturbation treatment step, (ii) in combination with a step comprising treatment with one or more hair growth-promoting agents.
  • the method of treating baldness or alopecia or promoting hair growth or thickness of hair comprising integumental perturbation (optionally in combination with a post-perturbation treatment step) in combination with a step comprising treatment with one or more hair growth-promoting agents results in hair follicle neogenesis, stimulation, activation or reorganization of existing hair follicles, the formation or an increase in NL, PEL, or PELA follicular structures, an increase in the numbers of vellus hairs, an increase in the numbers of terminal hairs, and/or an increase in the numbers of terminal hairs in the treated area.
  • pharmaceutical compositions for use in the hair growth-promoting agent treatment step are also provided herein.
  • the term "hair growth-promoting agent” refers to any agent that promotes hair growth or hair thickness, or is intended for such purpose, and/or treats a disease or condition associated with hair loss, or is intended for such purpose.
  • the hair growth-promoting agent is an agent that promotes, or is intended to promote, the transition of vellus hair to terminal hair.
  • the hair growth-promoting agent increases vellus hair growth.
  • the hair growth-promoting agent increases terminal hair growth.
  • the hair growth-promoting agent increases the ratio of terminal-to-vellus hair on an area of skin of a subject.
  • the hair growth-promoting agent maintains terminal hair growth, i.e. helps prevent miniaturization of terminal hairs.
  • the hair growth-promoting agent increases the number of anagen hairs or increases anagen hair growth.
  • the hair growth-promoting agent increases the ratio of anagen-to-teleogen hair on an area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein promotes growth of hair on an area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein increases the amount or thickness of hair on a treated area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein results in an increase in the amount of vellus hair on a treated area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein results in an increase in the amount of terminal hair on a treated area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein results in the maintenance of terminal hair growth, i,e. helps prevent miniaturization of terminal hairs.
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein results in an increase in the ratio of terminal-to-vellus hair on a treated area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein results in an increase in the amount of anagen hair or increases anagen growth on a treated area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein results in an increase in the ratio of anagen-to-telogen hair on a treated area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein results in hair follicle neogenesis in a treated area of skin of a subject.
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein results in an increased number of hair follicles in a treated area of skin of a subject.
  • the method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents results in formation of new hair follicles with nonvellus-sized hair shafts (i.e ., hair shafts with diameters equal to or greater than 30 microns in diameter) in a treated area of skin of a subject.
  • nonvellus-sized hair shafts i.e ., hair shafts with diameters equal to or greater than 30 microns in diameter
  • a method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents provided herein results in an increased number of stimulated and activated hair follicles, such as pre-existing hair follicles, in a treated area of skin of a subject.
  • the method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents results in an increased number of pre-existing hair follicles with nonvellus-sized hair shafts in a treated area of skin of a subject.
  • the method of integumental perturbation in combination with a post-perturbation treatment step in combination with a step comprising treatment with one or more hair growth-promoting agents results in the presence and/or increased numbers of NL, PEL, and PELA follicular structures.
  • compositions and treatment methods comprising hair growth-promoting agents are described in Section 5.3 infra , however, the invention is not to be so limited, and any pharmaceutical composition may be used in accordance with the hair growth-promoting treatment steps described herein.
  • integumental perturbation refers to any treatment of the skin and/or other tissues of the integumentary system that results in debriding, peeling, or wounding, or other perturbation of the skin.
  • a treatment with integumental perturbation refers to any treatment that results in an increase in the number of neogenic-like (NL) hair follicles, stimulated or activated or reorganized follicles, such as pre-existing-like (PEL) or pre-existing-like, attached (PELA) follicular structures (as these terms are described herein; see e.g., Section 5.8.4 infra ).
  • a treatment with integumental perturbation refers to any treatment that results in an increase in the number of vellus hairs or terminal hairs or anagen hairs.
  • Integumental perturbation can be achieved by any means known in the art or described herein or that may become available in the future, such as, for example, using chemical, mechanical, physical, or electromagnetic means.
  • the integumental perturbation treatment increases the number of NL, PEL, or PELA follicular structures in an area of skin adjacent to the integumentally perturbed skin site.
  • the integumental perturbation treatment increases the number of NL, PEL, or PELA follicular structures in the integumentally perturbed skin site, for example, beneath the site of integumental perturbation. In another embodiment, the integumental perturbation treatment increases the number of NL, PEL, or PELA follicular structures in the integumentally perturbed skin site and in an area of skin adjacent to the integumentally perturbed skin site. In one embodiment, integumental perturbation comprises disrupting the skin of the subject (for example, resulting in the induction of re-epithelialization of the skin of the subject). In some embodiments, a certain area of the epithelium is partially or wholly disrupted.
  • a certain area of both the epithelium and stratum corneum are partially or wholly disrupted.
  • skin disruption and re-epithelialization including methods for disrupting skin and inducing and detecting re-epithelialization, see PCT Publication Nos. WO 2008/042216 and WO 2006/105109 , each of which is incorporated herein by reference.
  • Integumental perturbation can be used to induce, for example, a burn, excision, dermabrasion, full-thickness excision, blister, or other form of abrasion or wound.
  • integumental perturbation can be achieved, for example, using phenol, trichloroacetic acid, ascorbic acid, an enzyme that cleaves the basement membrane ( Fein et al., Dermatol Surg. 2005;31(2):139-47 ); discussion 147-8., or an inflammatory agent.
  • a chemical means of integumental perturbation is by inducing inflammation, which can be accomplished by, e.g., application of an adjuvant.
  • the adjuvant is one or more of sodium dodecyl sulfate, aluminum salts, monophosphoryl lipid A, or cetyl triammonium bromide (CTAB).
  • inflammation is induced by application of a cytokine (e.g., IL-1beta).
  • inflammation is induced by application of an antigen (e.g. tetanus toxoid).
  • integumental perturbation include, for example, dermabrasion (DA), particle-mediated dermabrasion (PMDA), microdermabrasion, microneedles, microneedle rollers, dermatome planning (e.g., dermaplaing), a coring needle, a puncture device, a punch tool or other surgical tool, suction tool or instrument, use of sandpaper, a felt wheel, ultrasound, sonoporation, supersonically accelerated mixture of saline and oxygen, tape-stripping, spiky patch, or peels, or surgical treatments (e.g ., biopsy, skin graft, hair transplant, cosmetic surgery, strip harvesting, scalp reduction, hair transplant, follicular unit extraction (FUE), robotic FUE, etc .).
  • DA dermabrasion
  • PMDA particle-mediated dermabrasion
  • microdermabrasion e.g., microdermabrasion
  • microneedles e.g., microneedles
  • microneedle rollers e.g.,
  • Electromagnetic means of integumental perturbation include, for example, use of heat or thermal injury.
  • electromagnetic means of integumental perturbation is by laser ( e.g., using lasers, such as those that deliver ablative, non-ablative, fractional, non-fractional, superficial or deep treatment, and/or are CO 2 -based, or erbium-YAG-based, erbium-glass, neodymium:yttrium aluminum garnet (Nd:YAG) laser, etc. ), a low-level laser therapy treatment (e.g. , HairMax), or laser abrasion.
  • the integumental perturbation is carried by "photo-biostimulation" of the hair follicles.
  • the Hairmax Lasercomb or the Leimo laser are non-limiting examples of devices that can be used to stimulate growth of hair, and can be used alone, in combination with another form of integumental perturbation described herein, or in combination with a treatment described in Section 5.2-5.4 or elsewhere herein or known in the art.
  • Integumental perturbation can also be achieved through, for example, the use of irradiation, such as, e.g., visible, infrared, ultraviolet, radio, or X-ray irradiation.
  • integumental perturbation is by light energy, such as described in Leavitt et al., 2009, Clin. Drug. Invest. 29:283-292 , or intense pulsed light.
  • Electrical or magnetic means of disruption of the epidermis can be achieved, for example, through the application of an electrical current, through electroporation, radio frequency (RF) ablation, electrology, low voltage electric current, iontophoresis, electrophoresis, or any other form of electromagnetic disruption.
  • RF radio frequency
  • Electric or magnetic means can also include the induction of an electric or a magnetic field, or an electromagnetic field.
  • an electrical current can be induced in the skin by application of an alternating magnetic field.
  • a radiofrequency power source can be coupled to a conducting element, and the currents that are induced will heat the skin, resulting in an alteration or disruption of the skin.
  • a fractional like hole pattern (similar to that achieved with a fractional laser or full thickness excision) is achieved with using an array of punch biopsy needles.
  • 1-mm punch biopsies can be arranged with 1-mm hole spacing.
  • the cored skin samples can be removed and, thus, an effect approximating the full thickness excision model is invoked within each hole.
  • microneedles e.g ., 19 or 21 gauge needles
  • micro-coring needles could be used.
  • integumental perturbation is accomplished using a microneedle array.
  • the microneedle array is in the form of a roller or flat plate.
  • the microneedle array can disrupt a skin area of 1.5 cm x 1.5 cm to 15 cm x 15 cm.
  • the microneedle array can disrupt skin at a depth of 100 microns to 4000 microns.
  • the microneedle array has hollow needles.
  • the microneedle array top has a luer-lock fitting that can accommodate a syringe to deliver drug.
  • the volume of the syringe is 1 ml to 3 ml.
  • a device or method of integumental perturbation described in US Patent Application Publication Nos. US 2011-0130711 , US 2011-0130748 , or US 2011-0130706 , each published June 2, 2011, or International Patent Application Publication No. WO 11/123218, published June 10, 2011 , each of which is incorporated by reference herein in its entirety, may be used in accordance with the invention.
  • a technique of integumental perturbation for use in the invention excludes freezing of the skin. In some embodiments, a technique of integumental perturbation for use in the invention includes freezing of the skin.
  • a method of treatment - either the integumental perturbation step, and/or post-perturbation treatment(s) step, and/or hair growth-promoting agent(s) treatment step - is carried out over a small area of skin, e.g., 1x1 cm, or 1.5x1.5 cm, or 2x2 cm, or 2.5x2.5 cm, or 3x3 cm or more).
  • the method of treatment is carried out over a larger area of skin, such as, e.g, an entire balding area of scalp.
  • treatment of a small area of skin is followed by treatment of a larger area of skin.
  • a step or steps of the treatment is carried out over alternating areas of skin, by applying, for example, a mesh or grid-like covering to the area to be treated so that areas contacted with the treatment alternate with areas that are not contacted with the treatment.
  • integumental perturbation is by dermabrasion (also referred to herein as "DA"), a well-established dermatological procedure that has been used for decades as a skin resurfacing technique ( Grimes, 2005, Microdermabrasion. Dermatol Surg 31:1351-1354 ). While the popularity of mechanical dermabrasion has decreased in recent years with the advent of laser-based procedures, dermabrasion is still used for removing facial scars resulting from acne and other trauma. Small, portable mechanical dermabrasion equipment uses interchangeable diamond fraises operated at different rotation speeds to remove the epidermis and dermis to differing skin depth levels.
  • Dermabrasion may be carried out using any technique known in the art, described elsewhere herein (e.g., as described in the examples), or that becomes available in the future.
  • dermabrasion may be carried out using standard DA with aluminum oxide crystals using the Aseptico Econo-Dermabrader, Advance Microderm DX system, or M2-T system; standard DA with Bell Hand Engine with diamond fraise; wire brush; etc.
  • dermabrasion can be carried out using a hand-held dermabrader with a standard grit diamond fraise to achieve pinpoint capillary bleeding (estimated depth 100-150 microns, not anticipated to cause scarring).
  • the method of dermabrasion is alumina-, silica- or ice-based dermabrasion (as described by, e.g., Weber, U.S. 6,764,493 ; U.S. 6,726,693 ; and U.S. 6,306,119 ).
  • DA is carried out using an abrasive wheel.
  • DA with an abrasive wheel is used in order to achieve pinpoint bleeding.
  • dermabrasion may be carried out using an abrasive wheel to achieve larger globules of bleeding and frayed collagen.
  • Non-powered devices such as abrasive cloths can also be used to achieve the dermabrasion, with the optional achievement of the same endpoint.
  • DA is accomplished using a device typically used for microdermabrasion (also referred to herein as "MDA").
  • MDA microdermabrasion
  • a microdermabrasion device is used to remove a greater depth and/or area of skin than is typical for microdermabrasion.
  • the microdermabrasion device is used under sterile conditions.
  • dermabrasion is achieved by using a device for microdermabrasion to the point where treatment is stopped upon the observation of pinpoint bleeding, which signals the removal of the stratum corneum and epidermis into the papillary dermis.
  • dermabrasion is achieved by using a device for microdermabrasion to the point where treatment is stopped upon the observation of larger globules of bleeding and frayed collagen, which signals the removal of the stratum corneum and epidermis into the deeper papillary and reticular dermis.
  • this extended use is reduced by using a microdermabrasion device with increased output pressure and increased abrasion particle size, which may accelerate the skin removal process.
  • DA is accomplished by removal of surface skin by particle bombardment (also referred to herein as "particle mediated dermabrasion" (“PMDA”)), for example, with alumina-, ice- or silica-based particles.
  • particle bombardment also referred to herein as "particle mediated dermabrasion” (“PMDA)
  • PMDA particle mediated dermabrasion
  • micron-sized particles are propelled toward the surface of the skin via short strokes of a handpiece, such as a particle gun, as known in the art.
  • the velocity of particles is controlled through positive or negative pressure.
  • the depth of skin removed by particle bombardment DA (e.g., PMDA) is a function of the volume of particles impacting the skin, the suction or positive pressure, the speed of movement of the handpiece, and the number of passes per area of the skin.
  • a technique of dermabrasion for use in the invention excludes freezing of the skin. In some embodiments, a technique of dermabrasion for use in the invention includes freezing of the skin. Freezing is done with wheel dermabraders to make the skin more firm for a more controlled and consistent dermabrarding.
  • a dermabrasion tip that converts the rotational output of conventional dermabraders to a reciprocating motion. Additionally, the present dermabrasion tip uses an angle offset in order to improve ergonomics for the user. Embodiments of the present invention have several advantages over conventional dermabrasion tips including improved ergonomics, less blood and splatter, better clinician control, better suitability for use in areas of thinning hair, being hair-sparing, and use as a single use disposable unit.
  • FIG 9 Depicted in Figure 9 is an embodiment of a dermabrasion tip 220 that can be used with conventional dermabraders and which converts the rotational motion of a standard dermabrader to a reciprocating motion. As depicted, this embodiment is designed to be compatible as a direct replacement for a standard dermabrasion tip and thus, can be used with a standard dermabrasion hand piece 222.
  • An example of a standard dermabrader with which the present dermabrasion tip can be used is depicted in Figure 10 , which is a Torque Plus+ dermabrader, Model AEU-12C, manufactured by Aseptico, Inc. in Woodinville, WA.
  • the dermabrader typically includes a control unit 223, a dermabrasion hand piece 222, and a cord 224 that connects the hand piece 222 to the control unit 223.
  • the present dermabrasion tip 220 simply fits over the front end 225 of a conventional dermabrasion hand piece 222 thereby converting the hand piece's rotational motion to a reciprocating motion.
  • the dermabrasion tip 220 houses a gear/linkage converting transmission 226.
  • a first pair of bevel miter gears 228 converts the rotational output of the hand piece 222 to rotational output that is essentially orthogonal to the direction of rotation of the drive unit of the hand piece 222.
  • the gears 228 can be constructed of Nylon, Acetal, or other suitable durable low-friction plastic, can be approximately 6.35 mm in diameter, and will typically have approximately 1.9 teeth/mm.
  • the first set of bevel gears 228 is driven by a drive shaft 230 that can be made, for example, from stainless steel and is approximately 2.36 mm in diameter.
  • Such a drive shaft 230 is suitable for insertion into the front end 225 of the hand piece 222 for connection to the hand piece's drive unit.
  • the first set of bevel gears 228 connect to a linkage assembly 232 that is similar to a locomotive linkage.
  • the linkage assembly 232 converts the orthogonal rotational motion of the conventional hand piece 222 to orthogonal reciprocating motion.
  • the linkage assembly 232 includes an input drive wheel 234, an output drive wheel 236, and at least one coupling rod 238.
  • a first end of the coupling rod 238 attaches to an edge portion of the input drive wheel 234 and the second end of the coupling rod 238 attaches to an edge portion of the output drive wheel 236.
  • the input drive wheel 234 rotates through a radius that is smaller than the diameter of the output drive wheel 236. Therefore, as the input drive wheel 234 completes 360 degrees of rotation, the output drive wheel 236 reciprocates through a motion of less than +/- 180 degrees. That is, the output drive wheel 234 never completes a complete 360 degree rotation and instead reciprocates back in forth as indicated by arrow 242.
  • the diameters of the input drive wheel 234 and output drive wheel 236 of the linkage assembly 32 one can adjust the reciprocating swing downward from +/- 180 degrees.
  • the input drive wheel 234 is approximately 6.35 mm inches in diameter and the output drive wheel 236 is approximately 9.53 mm in diameter and the coupling rod 238 is approximately 12.7 mm in length. Preferably, this provides for approximately +/- 45 degrees of reciprocating output.
  • the diameters of the input and output drive wheels, 234, 236, and/or the length of the coupling rod 238, can be changed in order to change the degree of reciprocating motion, which can range anywhere from 1 degree to 179 degrees.
  • the linkage assembly 232 can be constructed, for example, of Nylon, Acetal, or other suitable durable low-friction plastics.
  • the reciprocating output drive wheel 236 of the linkage assembly 232 connects to a second pair of similar (size, material, pitch, etc.) bevel miter gears 244 that convert the reciprocating output of the linkage assembly 232 to a reciprocating output that is, in the present embodiment, at an angle of approximately 45 degrees to the elongated axis of the hand piece 222.
  • the 45 degree reciprocating output connects to a second drive shaft 246, which, for example, can be made of stainless steel.
  • This second drive shaft 246 is connected to a circular pad 248, which can be made, for example, of polypropylene, and which can have a diameter of approximately 12.7 mm.
  • abrasive disk 250 Supported by pad 248 is an abrasive disk 250, which may be composed of bonded aluminum oxide particles with a course CAMI grit of 24, 30, or 36.
  • Johnson Abrasives Jaffery NH Wet-Kut water proof abrasive backed clothed may be adequately secured to the support pad with very-high-bond tape such as 3M-4952.
  • the reciprocating motion of the second drive shaft 246 is transferred to the abrasive disk 250.
  • the diameters can be varied to achieve the desired transmission speed and torque conversions.
  • All of the transmission components described above may be housed in, for example, a polypropylene housing or a housing made of other suitable materials.
  • the housing can be approximately 63.5 mm in length with an external surface contoured to achieve maximum ergonomics.
  • the inside proximal diameter is designed to be approximately 15 mm, which allows the housing and hence, the entire dermabrasion tip 220 to be inserted onto the front end portion 225 of a conventional dermabrasion hand piece 222 as depicted in Figure 9 .
  • a co-molded low durometer thermoplastic rubber (TPR) or thermoplastic elastomer (TPE) insert 252 having an inside diameter of approximately 14.4 mm, is included on the inside of the dermabrasion tip 220.
  • TPR thermoplastic rubber
  • TPE thermoplastic elastomer
  • the present dermabrasion tip 220 includes an angle 256 of approximately 45 degrees between the longitudinal axis of the hand piece and the end effector. As previously discussed, such an angle improves ergonomics and allows the hand piece to be held more like a pen or artist paint brush. The added angle also improves clinician comfort and overall control. As will be readily apparent to those skilled in the art, different angles may be used to change the ergonomics of the dermabrasion tip.
  • the dermabrasion tip 220 can include an adjustable end effector such that the angle between the longitudinal axis of the hand piece 222 and the end effector can be adjusted by the clinician in order to better adapt the dermabrasion tip 220 to the clinician and/or patient and/or procedure being performed.
  • the second drive shaft 246 can include a plurality of notches 258. These notches 258 permit the second drive shaft 244 to flex, thereby allowing the abrasive disk 250 to conform to the skin surface.
  • Other ways to achieve conformability of the abrasive pad 250 to the skin surface include, but are not limited to, use of a ball and socket joint or a universal joint.
  • all the inexpensive plastic transmission parts previously described for use in a single use disposable dermabrasion tip can be made from stainless steel and incorporated into the body of a dermabrasion tip that can be reusable. Essentially, all the parts of the reciprocating dermabrasion tip would then be reusable with the exception of the abrasive disk, which could be peeled off after use and discarded. Thus, after the reusable dermabrasion tip is cleaned, a new abrasive disk could be attached prior to use.
  • the above-described dermabrasion tip can be packaged in a kit with a tube (or other similar container) containing a pharmaceutical composition for use in conjunction with the procedure, examples of which include the post-perturbation treatments described in Section 5.2, hair growth-promoting agents described in Section 5.3, other drugs described in Section 5.4, or described elsewhere herein or otherwise known in the art.
  • the kit would include all the necessary consumables to perform the follicular procedure in the clinic.
  • the present invention is directed to a method of inducing hair growth that comprises disrupting a skin surface with a dermabrasion tip disclosed herein and then applying one or more post-perturbation treatment described in Section 5.2, one or more hair growth-promoting agents described in Section 5.3, other drugs described in Section 5.4, or described elsewhere herein or otherwise known in the art.
  • integumental perturbation is by laser treatment.
  • Exemplary laser treatments for integumental perturbation include or fractional laser (e.g., Fraxel), laser abrasion, erbium-YAG laser, erbium-glass laser, Ultrapulse CO 2 fractional laser, Ultrapulse CO 2 ablative laser, Smooth Peel Full-ablation Erbium laser (Candela), or neodymium:yttrium aluminum garnet (Nd:YAG) laser. Any other laser treatment described herein, known in the art, or described in the future may also be used in the methods described herein.
  • a laser treatment is chosen in which the integumental perturbation achieved most resembles that achieved by dermabrasion (for example, a dermabrasion method described herein).
  • integumental perturbation by laser treatment is by a fractional laser. See, e.g ., the laser treatments described in U.S. Provisional Application Nos. 61/262,820 , 61/262,840 , 61/262,831 , each of which is incorporated herein by reference in its entirety.
  • One example of a fractional laser treatment is treatment with an erbium-YAG laser at around 1540 nm or around 1550 nm (for example, using a Fraxel® laser (Solta Medical)).
  • Treatment with an erbium-YAG laser at 1540 or 1550 nm is typically non-ablative, and pinpoint bleeding typical of laser treatment is not observed since the stratum corneum is left intact.
  • the column of dead (epidermal and/or dermal) cells in the path of the laser treatment is termed a "coagulum.”
  • integumental perturbation by laser treatment is by a fractional laser, using, e.g., a CO 2 laser at 10,600 nm.
  • Treatment with a CO 2 laser at 10,600 nm is typically ablative, and typically leads to the appearance of pinpoint bleeding.
  • the laser is a fractional erbium-glass laser, used at, e.g., 1550 nm.
  • a subject receives one or more (2-10 or more) treatments with a 1550 nm fraction Er:Glass Laser at 2-week intervals using a 5-10 mm tip, 6 mJ pulse energy, 800 spot/cm 2 density, and static mode, as described in Lee et al., 2011, Journal of the European Academy of Dermatology and Venereology 25:1450-1454 , which is incorporated by reference herein in its entirety. See also Kim et al., 2011, Dermatol Surg 37:41-51 , also incorporated by reference herein in its entirety.
  • a standard CO 2 or erbium-YAG or erbium-glass laser can be used to create superficial and, optionally, broad based, integumental perturbation similar to dermabrasion (discussed below).
  • the pinpoint bleeding clinical endpoint may not be achieved due to the coagulation properties of (particularly non-ablative) lasers, use of a laser has an advantage making it possible to select the specific depth of skin disruption to effectively remove the stratum corneum and epidermis, or portions thereof.
  • the laser treatment is ablative.
  • full ablation of tissue is generated by the targeting of tissue water at wavelengths of 10,600 nm by a CO 2 laser or 2940 nm by an erbium-YAG laser.
  • the epidermis is removed entirely and the dermis receives thermal tissue damage.
  • the depth of tissue ablation may be a full ablation of the epidermis, or a partial ablation of the epidermis, with both modes causing adequate wounding to the skin to induce the inflammatory cascade requisite for regeneration.
  • the depth of ablation may extend partially into the dermis, to generate a deep wound.
  • the denuded skin surface is then treated with one or more hair growth-promoting agents; alternatively, the one or more hair growth-promoting agents can be delivered into the skin after the initial re-epithelialization has occurred already, to prevent clearance and extrusion of the hair growth-promoting agent-containing depots from the tissue site by the biological debris-clearance process.
  • one or more hair growth-promoting agents is delivered by a sustained release depot that is comprised of biocompatible, bioabsorbable polymers that are compatible to tissue.
  • the standard full thickness excision model is created using scissors or with a scalpel in animal models (see, also, the examples of Sections 28-30 and 32 in International Patent Application Publication No. WO 2011/031990 , which is incorporated by reference herein in its entirety).
  • Full thickness excision while contemplated for use herein, carries with it the risk of scarring.
  • various fractional laser modalities could be used to achieve a similarly deep disruption on a grid pattern.
  • a fractional laser can be use to "drill," for example, 1-mm diameter holes with a 1-mm hole spacing (the fractional laser can make holes of smaller dimensions).
  • the integumental perturbation by laser is non-fractional and ablative.
  • the non-fractional, ablative integumental perturbation is by full bulk ablation, wherein the tissue of the entire area of treatment is ablated.
  • the non-fractional, ablative integumental perturbation by bulk ablation is over an area of 1.5 cm x 1.5 cm to 15 cm x 15 cm.
  • the non-fractional, ablative integumental perturbation by bulk ablation is accomplished at 10,600 nm using a carbon dioxide laser.
  • the non-fractional, ablative integumental perturbation by bulk ablation is accomplished at 2940 nm using a Erbium-YAG laser.
  • the laser treatment is fractional and ablative.
  • fractional tissue ablation can be achieved using a CO 2 laser at 10,600 nm or an erbium-YAG laser at 2940 nm (e.g., the Lux 2940 laser, Pixel laser, or Profractional laser).
  • the lasing beam creates micro-columns of thermal injury into the skin, at depths up to 4 mm and vaporizes the tissue in the process.
  • Ablative treatment with a fractional laser leads to ablation of a fraction of the skin leaving intervening regions of normal skin intact to rapidly repopulate the epidermis. Approximately 15%-25% of the skin is treated per session.
  • micro thermal zones can be varied to create a dense "grid" of injury columns surrounded by intact skin and viable cells.
  • the density of the grid on the treatment area plays an important role. The denser the grid, the more the thermal injury and the type of injury begins to approximate full ablation. Therefore, it is appreciated that there may be an "optimum" MTZ density that is appropriate for use in the methods disclosed herein.
  • one or more hair growth-promoting agents is delivered into the dermis immediately after wounding, or after initial re-epithelialization has occurred.
  • the fractional, ablative integumental perturbation results in fractional ablation of the skin at a depth between 100 microns and 4000 microns into the skin, or results in fractional ablation of the skin at a depth approximating the depth of a full-thickness excision wound.
  • the fractional, ablative integumental perturbation results in fractional ablation of the skin over an area of 1.5 cm x 1.5 cm to 15 cm x 15 cm.
  • the fractional, ablative integumental perturbation results in fractional ablation of the skin at a depth density of the micro-thermal zones of the fractional ablation approximates that of a full bulk ablation of the entire area of treatment.
  • the fractional, ablative integumental perturbation is by full bulk ablation, wherein the tissue of the entire area of treatment is ablated.
  • the fractional, ablative integumental perturbation by bulk ablation is over an area of 1.5 cm x 1.5 cm to 15 cm x 15 cm.
  • the fractional, ablative integumental perturbation by bulk ablation is accomplished at 10,600 nm using a carbon dioxide laser.
  • the fractional, ablative integumental perturbation by bulk ablation is accomplished at 2940 nm using a Erbium-YAG laser.
  • the mode of laser treatment is non-ablative, wherein the stratum corneum and the epidermis are intact after treatment, with the dermis selected for the deep thermal treatment required for the requisite injury to tissue.
  • This can be accomplished by cooling the epidermis during the laser treatment.
  • the depth of treatment may be 1 mm to 3 mm into the skin.
  • contact cooling such as a copper or sapphire tip.
  • Lasers that are non-ablative have emission wavelengths between 1000-1600 nm, with energy fluences that will cause thermal injury, but do not vaporize the tissue.
  • the non-ablative lasers can be bulk, wherein a single spot beam can be used to treat a homogenous section of tissue. In some embodiments, multiple treatments are required to achieve the desired effect. In one embodiment, one or more hair growth-promoting agents is delivered deep into the dermis in polymeric micro-depots and released in a sustained fashion.
  • Lasers that are non-ablative include the pulsed dye laser (vascular), the 1064 Nd:YAG laser, or the erbium-YAG laser at 1540 nm or 1550 nm ( e.g ., the Fraxel® laser).
  • the mode of laser treatment is fractional and non-ablative.
  • Treatment with a fractional, non-ablative laser leads to perturbation of a fraction of the skin, leaving intervening regions of normal skin intact to rapidly repopulate the epidermis. Approximately 15%-25% of the skin is treated per session.
  • the skin barrier function is maintained, while deep thermal heating of dermis can occur. Thus, zones of dermis and epidermis are coagulated and the stratum corneum is left essentially intact.
  • This process has been coined "fractional photothermolysis" and can be accomplished, e.g ., using the Erbium-YAG laser with an emission at or around 1540 nm or 1550 nm.
  • one or more hair growth-promoting agents is delivered immediately after the tissue injury, deep into the dermis.
  • a combination of bulk and fractional ablation modes of tissue injury are used.
  • the fractional, non-ablative integumental perturbation by laser is performed by use of an Erbium-YAG laser at 1500-1590 nm.
  • the mode of laser treatment for, e.g ., a Caucasian male 30-50 years old is fractional and non-ablative using an erbium-YAG laser at 1550 nm, with the following settings: 50-70 J/cm 2 , treatment level 8-10 (density of the "dots"), with 8 passes.
  • the laser device can be equipped with a touch pad screen that offers the operator a menu of options for setting the parameters for operating the laser to promote hair growth.
  • the device can be programmed to offer the operator selections for hair growth vs. removal, choice of skin color, hair follicle density, power settings, etc.
  • a treatment comprising use of a laser includes administration to the skin of a compound absorbing light at wavelengths between 1000-1600 nm for the purpose of efficient channeling of light to heat energy.
  • This method of channeling energy may cause micro-zones of thermal injury within the skin.
  • the compound may be delivered to the skin homogenously in the treatment zone, then subsequently irradiated with a non-ablative laser to efficiently capture the vibrational energy of the infrared beam. This method may result in evenly distributed and deep thermal injury, without causing tissue vaporization.
  • a treatment comprising use of a laser includes administration of one or more hair growth-promoting agents that is encapsulated in matrices that are highly hydrophilic and charged, for example, linked to the dermis by covalent or ionic bonding to prevent the matrices from being cleared by phagocytosis, as part of the wound healing process.
  • a treatment comprising use of a laser includes the step of placing a biocompatible, synthetic skin substitute on the newly created wound, especially if the wound is deep, covers large area and is bulk ablated. This process can help minimize or prevent the rapid wound contraction that occurs after loss of a large area of tissue, frequently culminating in scar tissue formation and loss of skin function.
  • the biocompatible synthetic skin substitute is be impregnated with depots of a slow releasing hair growth-promoting agent formulation described herein. This method of treatment may enable treating a large bald area on the scalp in one session at the treatment clinic.
  • other molecules are also co-eluted at the site through the skin substitute, such as, e.g ., anesthetics and antibiotics, to prevent further pain and minimization of infection, or any other compound described herein.
  • the skin substitute in the presence or absence of one or more hair growth-promoting agents and/or other compounds described herein, may also be pre-cooled and applied to the wound to provide a feeling of comfort to the patient. This mode of treatment may prevent the one or more hair growth-promoting agents or other compound from being cleared away from the wound site as the wound heals.
  • integumental perturbation can be carried out in a fashion that exerts control over the extent of perturbation and/or control over the way in which the integumentally perturbed skin heals.
  • the integumental perturbation method causes only superficial wounding to the area of skin on which hair growth is desired.
  • the extent of wounding is minimized by controlling the depth of perturbation.
  • the integumental perturbation procedures described herein can be controlled to limit perturbation to part or all of the epidermis, to part or all of the stratum corneum, or deeper into the papillary dermis, reticular dermis, and/or hypodermis.
  • the occurrence of pinpoint bleeding would indicate removal of the stratum corneum, epidermis (or part thereof) and portions of the upper layer of the dermis, such as the superficial papillary dermis.
  • the occurrence of increased bleeding would indicate deeper penetration (and thus perturbation) into the deeper papillary dermis and reticular dermis layer.
  • the integumental perturbation does not remove the epidermis. In some embodiments, the integumental perturbation achieves removal of part of the epidermis. In some embodiments, integumental perturbation removes the entire epidermis. In some embodiments, the integumental perturbation removes all of the epidermis and part of the dermis. In some embodiments, integumental perturbation removes part of the stratum corneum. In some embodiments, integumental perturbation removes the stratum corneum. In some embodiments, integumental perturbation removes part of the papillary dermis. In some embodiments, integumental perturbation removes part of the more superficial papillary dermis.
  • integumental perturbation removes part of the deeper papillary dermis. In some embodiments, integumental perturbation removes the papillary dermis. In some embodiments, integumental perturbation removes the reticular dermis, or part of the reticular dermis.
  • the depth of integumental perturbation depends on the thickness of the skin at a particular treatment area. For example, the skin of the eyelid is significantly thinner than that of the scalp. The occurrence of pinpoint bleeding indicates that the epidermis and portions of the dermis have been removed. Deeper penetration can results in much more bleeding, and the perturbation can go as deep as the hypodermis.
  • integumental perturbation is done to a clinical endpoint of pinpoint bleeding.
  • the depth reaches the level of blood vessels of the follicular papilla.
  • the depth does not go deeper than the level of blood vessels of the capillary loops in the dermal papilla, e.g., the area of papillary dermis in between rete pegs (see Figure 23 ).
  • the integumental perturbation does not penetrate the dermis.
  • the integumental perturbation does not completely remove all, or in some embodiments, most, of the hair follicles in an area of treated skin.
  • the integumental perturbation does not penetrate the reticular dermis.
  • the integumental perturbation does not penetrate more than halfway through the papillary dermis.
  • integumental perturbation by one or more of the aforementioned methods is to a skin depth of between 5 and 40 ⁇ m, 40 and 100 ⁇ m, 30 and 200 ⁇ m, 50 and 150 ⁇ m, 70 and 130 ⁇ m, 80 and 120 ⁇ m, 90 and 110 ⁇ m, 95 and 105 ⁇ m, or 100 and 150 ⁇ m.
  • integumental perturbation by one or more of the aforementioned methods is to a skin depth of at least 30 ⁇ m. In some embodiments, integumental perturbation by one or more of the aforementioned methods is to a skin depth of 30 ⁇ m. In some embodiments, integumental perturbation is to a skin depth of 50 ⁇ m. In some embodiments, integumental perturbation by one or more of the aforementioned methods is to a skin depth of 60 ⁇ m. In some embodiments, integumental perturbation is to a skin depth of 30-100 ⁇ m. In some embodiments, integumental perturbation is to a skin depth of 60-100 ⁇ m.
  • integumental perturbation is to a skin depth of 60-200 ⁇ m. In some embodiments, integumental perturbation is to a skin depth of 100 ⁇ m. In some embodiments, integumental perturbation is to a skin depth of 100-150 ⁇ m. In some embodiments, integumental perturbation is to a skin depth of 150 ⁇ m. In some embodiments, integumental perturbation is to a skin depth of 100-200 ⁇ m. In some embodiments, integumental perturbation is to a skin depth of 30-200 ⁇ m.
  • integumental perturbation is to a skin depth of 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 ⁇ m.
  • the maximum depth of integumental perturbation is to, e.g., 30, 40, 50, 60, 70, 80, 85, 90, 95, 100, 105, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 ⁇ m.
  • integumental perturbation is to a skin depth of 100-500 ⁇ m. In some embodiments, integumental perturbation is to a skin depth of less than 500 ⁇ m. In some embodiments, integumental perturbation is to a skin depth of 500-1000 ⁇ m. In some embodiments, integumental perturbation is to a maximum skin depth of about 1 mm. In some embodiments, integumental perturbation is to a skin depth of about 1 mm or more. In some embodiments, integumental perturbation is to a maximum skin depth of about 2 mm. In some embodiments, integumental perturbation is to a skin depth of about 2 mm or more.
  • integumental perturbation is to a skin depth of 1 mm to 3 mm. In some embodiments, integumental perturbation is to a skin depth of 1 mm to 5 mm. In a particular embodiment, the depth of integumental perturbation does not exceed 500 ⁇ m. In a particular embodiment, the depth of integumental perturbation does not exceed 1 mm. In a particular embodiment, the depth of integumental perturbation does not exceed 2 mm
  • integumental perturbation is not by microdermabrasion. In some embodiments, integumental perturbation is not by full thickness excision. In some embodiments, integumental perturbation is by partial thickness excision. In some embodiments, integumental perturbation is not partial thickness excision.
  • any of the above-described methods may be used to remove a precise amount of epidermal tissue.
  • the methods of controlled integumental perturbation described herein may be used to achieve:
  • the extent of integumental perturbation and, in some cases, the resultant wounding is reduced by controlling the size of the perturbed area of skin; for example, by making a series of small wounds to effect wounding of a large area rather than a single large wound.
  • the area of integumental perturbation can be of any desired size, for example, between 0-3 mm in width (e.g., 1 mm, 2 mm, 3 mm, or greater), 0-2 cm in width (e.g., 1 cm, 1.5 cm, and 2.0 cm), or greater (for example, up to 10%, 30%, 50%, 70%, 90%, or 100% of a subject's scalp or other area of hair growth, such as the eyebrow area).
  • the area of integumental perturbation can be interfollicular.
  • a method of integumental perturbation described herein induces a wound in the skin.
  • the wounded skin is healed by primary intention.
  • the wounded skin is healed by secondary intention.
  • the wounded skin is healed by tertiary intention.
  • the wounded skin is healed more slowly than usually indicated for that kind of wound. This may enhance scarless wound healing and/or prolong the period during which hair growth in the wounded area of skin is promoted.
  • compositions for administration to skin following (and optionally before or during) integumental perturbation may be used in the post-perturbation treatment steps described herein.
  • the post-perturbation pharmaceutical composition is formulated for topical administration to skin.
  • the post-perturbation treatment is administered to an area of the skin that will be, is being, or that has been subjected to integumental perturbation in accordance with a method described herein.
  • a post-perturbation treatment is a non-occlusive wound covering.
  • a post-perturbation treatment is administered in order to heal the integumentally perturbed skin by primary intention.
  • a post-perturbation treatment is administered in order to heal the integumentally perturbed skin by secondary intention.
  • a post-perturbation treatment is administered in order to heal the integumentally perturbed skin by tertiary intention.
  • a post-perturbation treatment is administered in order to heal the integumentally perturbed skin more slowly than usually indicated for that kind of wound. This may enhance scarless wound healing and/or prolong the period during which hair growth in the wounded area of skin is promoted.
  • a post-perturbation treatment promotes wound healing with no or minimal scarring.
  • a pharmaceutical composition for post-perturbation treatment is formulated for topical administration as a gel, hydrogel, emulsion, solution, suspension, cream, ointment, dusting powder, dressing, elixir, lotion, suspension, tincture, paste, powder, crystal, foams film, aerosol, irrigation, spray, suppository, stick, bar, ointment, bandage, wound dressing, microdermabrasion or dermabrasion particle, drop, transdermal patch, or dermal patch.
  • the post-perturbation pharmaceutical composition is an aqueous formulation (e.g.
  • compositions may be administered via any topical means of delivery known in the art.
  • the composition is administered as part of an article of manufacture, such as a bandage or other wound dressing, such as described in Section 5.5.2.1 infra.
  • the composition is administered using a drug delivery system, such as described in Section 5.5.4.3 infra.
  • the pharmaceutical composition for post-perturbation treatment contains an active ingredient or active ingredients, such as described in Sections 5.3 or 5.4 below.
  • the formulation of the pharmaceutical composition for post-perturbation treatment is varied in order to control the rate of release of active ingredients (where present) in the composition. This may be accomplished by, for example, varying the molecular fluidity of the carrier, without changing its hydrophobicity, such as by varying the petrolatum to mineral oil ratio.
  • the pharmaceutical formulation is an ointment, comprising petrolatum, mineral oil, and lanolin alcohol. Exemplary formulations prepared in accordance with such embodiments are provided in the Examples below.
  • release of active ingredients can be modulated by varying the hydrophobic/ hydrophilic ratio of the formulation, for example, by preparing a petrolatum/water emulsion. Exemplary formulations prepared in accordance with such embodiments are provided in the Examples below.
  • a composition for post-perturbation treatment is a hydrogel comprising the following components at the listed concentrations Citric Acid at 6% to 10%, 7% to 9%; or at 8%; CMC at 1% to 3%, 1.5% to 2.5%, or at 2%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%; Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; distilled Water to 100%; 10% NaOH to adjust pH; Allantoin at 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Alginate at 0.05% to 0.2%, 0.08% to 0.14%, or at 0.12%; and Glycerin at 5% to 15%, 7% to 12%, or at 10%.
  • a composition for post-perturbation treatment comprises the following components at the listed concentrations: Citric Acid at 6% to 10%, 7% to 9%; or at 8%; Sodium Hyaluronate at 1% to 3%, 1.5% to 2.5%, or at 2%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%; Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; distilled Water to 100%; 10% NaOH to adjust pH; Allantoin at 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Alginate at 0.05% to 0.2%, 0.08% to 0.14%, or at 0.12%; and Glycerin at 5% to 15%, 7% to 12%, or at 10%.
  • a composition for post-perturbation treatment comprises the following components at the listed concentrations: Citric Acid at 6% to 10%, 7% to 9%; or at 8%; Collagen at 1% to 3%, 1.5% to 2.5%, or at 2%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%; Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; distilled Water to 100%; 10% NaOH to adjust pH; Aloe Vera Gel at 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Alginate at 0.05% to 0.2%, 0.08% to 0.14%, or at 0.12%; and Glycerin at 5% to 15%, 7% to 12%, or at 10%.
  • a composition for post-perturbation treatment is an emollient cream which is comprised of a Phase I and a Phase II, Citric Acid at 10% to 20%, 12% to 18%, 14% to 16%, 15% to 17%, or at 16%; Hyaluronic Acid at 1% to 3%, 1.5% to 2.5%, or at 2%; Glycerin at 5% to 15%, 7% to 12%, or at 10%; Allantoin at 0.1% to 1%, 0.2% to 0.8%, 0.3% to 0.6%, 0.35% to 0.5%, at 0.4%, or at 0.32%; Sodium Chloride at 0.1% to 1%, 0.3% to 0.7%, or at 0.5%; Methyl Paraben at 0.1% to 0.3%, 0.15% to 0.25%, or at 0.2%, Propyl Paraben at 0.05 to 0.15%, 0.075 to 0.125% or at 0.1 % or at 0.096%; 10% NaOH to adjust the pH; and Water to 100%; and wherein Phase I and a Phase II,
  • the emollient cream further comprises Citric Acid at 6% to 10%, 7% to 9%; or at 8%; Hyaluronic Acid at 0.25% to 2.5%, 0.5% to 2%, 0.75% to 1.5%, or at 1%, Glycerin at 1% to 9%, 2% to 8%, 3% to 8%, 4% to 6%, or at 5%; Allantoin 0.05% to 0.3%, at 0.1 % to 0.2%, or at 0.16%; Sodium Chloride at 0.05% to 0.5%, 0.1% to 0.4%, 0.2% to 0.3%, or at 0.25%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%;Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; 10% NaOH to adjust the pH; Water to 100%; Soybean Oil at 5% to 15%, 7% to 12%, or at 10%; Hydrogenated Cottonseed Oil 5% to 15%
  • a composition for post-perturbation treatment comprises the following components at the listed concentrations: Citric Acid at 6% to 10%, 7% to 9%; or at 8%; CMC at 1% to 3%, 1.5% to 2.5%, or at 2%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%; Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; distilled Water to 100%; 10% NaOH to adjust pH; Allantoin at 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Alginate at 0.05% to 0.2%, 0.08% to 0.14%, or at 0.12%; and Glycerin at 5% to 15%, 7% to 12%, or at 10%.
  • a composition for post-perturbation treatment comprises the following components at the listed concentrations: Citric Acid at 6% to 10%, 7% to 9%; or at 8%; Sodium Hyaluronate at 1% to 3%, 1.5% to 2.5%, or at 2%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%; Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; distilled Water to 100%; 10% NaOH to adjust pH; Allantoin at 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Alginate at 0.05% to 0.2%, 0.08% to 0.14%, or at 0.12%; and Glycerin at 5% to 15%, 7% to 12%, or at 10%.
  • a composition for post-perturbation treatment comprises the following components at the listed concentrations: Citric Acid at 6% to 10%, 7% to 9%; or at 8%; Collagen at 1% to 3%, 1.5% to 2.5%, or at 2%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%; Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; distilled Water to 100%; 10% NaOH to adjust pH; Aloe Vera Gel at 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Alginate at 0.05% to 0.2%, 0.08% to 0.14%, or at 0.12%; and Glycerin at 5% to 15%, 7% to 12%, or at 10%.
  • a composition for post-perturbation treatment is an emollient cream which is comprised of a Phase I and a Phase II, wherein Phase I comprises Citric Acid at 10% to 20%, 12% to 18%, 14% to 16%, 15% to 17%, or at 16%; Hyaluronic Acid at 1% to 3%, 1.5% to 2.5%, or at 2%; Glycerin at 5% to 15%, 7% to 12%, or at 10%; Allantoin at 0.1% to 1%, 0.2% to 0.8%, 0.3% to 0.6%, 0.35% to 0.5%, at 0.4%, or at 0.32%; Sodium Chloride at 0.1% to 1%, 0.3% to 0.7%, or at 0.5%; Methyl Paraben at 0.1% to 0.3%, 0.15% to 0.25%, or at 0.2%, Propyl Paraben at 0.05 to 0.15%, 0.075 to 0.125% or at 0.1% or at 0.096%; 10% NaOH to adjust the pH; and Water to 100%; and
  • the emollient cream further comprises Citric Acid at 6% to 10%, 7% to 9%; or at 8%; Hyaluronic Acid at 0.25% to 2.5%, 0.5% to 2%, 0.75% to 1.5%, or at 1%, Glycerin at 1% to 9%, 2% to 8%, 3% to 8%, 4% to 6%, or at 5%; Allantoin 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Sodium Chloride at 0.05% to 0.5%, 0.1% to 0.4%, 0.2% to 0.3%, or at 0.25%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%;Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; 10% NaOH to adjust the pH; Water to 100%; Soybean Oil at 5% to 15%, 7% to 12%, or at 10%; Hydrogenated Cottonseed Oil 5% to 15%,
  • compositions for use in the post-perturbation treatments follow:
  • a composition comprising menthol at 0.1% to 0.5%, 0.1% to 0.3%, 0.15% to 0.25%, at about 0.2%, or at 0.206%; Citric Acid at 6% to 10%, 7% to 9%; or at 8%; CMC at 1% to 3%, 1.5% to 2.5%, or at 2%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%; Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; distilled Water to 100%; 10% NaOH to adjust pH; Allantoin at 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Alginate at 0.05% to 0.2%, 0.08% to 0.14%, or at 0.12%; and Glycerin at 5% to 15%, 7% to 12%, or at 10%.
  • a composition comprising Menthol at 0.1% to 0.5%, 0.1% to 0.3%, 0.15% to 0.25%, at about 0.2%, or at 0.206%; Citric Acid at 6% to 10%, 7% to 9%; or at 8%; Sodium Hyaluronate at 1% to 3%, 1.5% to 2.5%, or at 2%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%; Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; distilled Water to 100%; 10% NaOH to adjust pH; Allantoin at 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Alginate at 0.05% to 0.2%, 0.08% to 0.14%, or at 0.12%; and Glycerin at 5% to 15%, 7% to 12%, or at 10%.
  • a composition comprising menthol at 0.1% to 0.5%, 0.1% to 0.3%, 0.15% to 0.25%, at about 0.2%, or at 0.206%; Citric Acid at 6% to 10%, 7% to 9%; or at 8%; Collagen at 1% to 3%, 1.5% to 2.5%, or at 2%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%; Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; distilled Water to 100%; 10% NaOH to adjust pH; Aloe Vera Gel at 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Alginate at 0.05% to 0.2%, 0.08% to 0.14%, or at 0.12%; and Glycerin at 5% to 15%, 7% to 12%, or at 10%.
  • An emollient cream which is comprised of a Phase I and a Phase II, wherein Phase I comprises Menthol at 0.1% to 1%, 0.2% to 0.8%, 0.3% to 0.6%, 0.35% to 0.5% or at 0.4%; Citric Acid at 10% to 20%, 12% to 18%, 14% to 16%, 15% to 17%, or at 16%; Hyaluronic Acid at 1% to 3%, 1.5% to 2.5%, or at 2%; Glycerin at 5% to 15%, 7% to 12%, or at 10%; Allantoin at 0.1% to 1%, 0.2% to 0.8%, 0.3% to 0.6%, 0.35% to 0.5%, at 0.4%, or at 0.32%; Sodium Chloride at 0.1% to 1%, 0.3% to 0.7%, or at 0.5%; Methyl Paraben at 0.1% to 0.3%, 0.15% to 0.25%, or at 0.2%, Propyl Paraben at 0.05 to 0.15%, 0.075 to 0.125% or at 0.1 % or at 0.09
  • the emollient cream further comprises Menthol at 0.1% to 0.5%, 0.1% to 0.3%, 0.15% to 0.25%, at about 0.2%; Citric Acid at 6% to 10%, 7% to 9%; or at 8%; Hyaluronic Acid at 0.25% to 2.5%, 0.5% to 2%, 0.75% to 1.5%, or at 1%, Glycerin at 1% to 9%, 2% to 8%, 3% to 8%, 4% to 6%, or at 5%; Allantoin 0.05% to 0.3%, at 0.1% to 0.2%, or at 0.16%; Sodium Chloride at 0.05% to 0.5%, 0.1% to 0.4%, 0.2% to 0.3%, or at 0.25%; Methyl Paraben at 0.05% to 0.15%, or at 0.1%;Propyl Paraben at 0.01 to 0.1%, 0.02 to 0.08%; 0.03% to 0.06%, or 0.05%; 10% NaOH to adjust the pH; Water to 100%; Soybean Oil
  • the post-perturbation pharmaceutical composition is formulated as an aqueous hydrogel.
  • the aqueous hydrogel comprises Carbopol 980, methyl paraben, propyl paraben, propylene glycol, glycerine, and water.
  • a hydrogel formulation comprises citric acid, CMC, methyl paraben, propyl paraben, allantoin, alginate, and water. Exemplary formulations prepared in accordance with such embodiments are provided in the Examples below.
  • a hydrogel has the following composition: glycerol, carboxymethyl cellulose, allantoin, sodium alginate, methyl paraben, propyl paraben, water (Q.S.), and sodium hydroxide (pH adjusted to 6.5-7.5).
  • glycerol carboxymethyl cellulose
  • allantoin sodium alginate
  • methyl paraben methyl paraben
  • propyl paraben water
  • sodium hydroxide pH adjusted to 6.5-7.5
  • a hydrogel contains approximately 75%, 80%, 85%, 90%, or 95% water. In a particular embodiment, the hydrogel contains 90% water.
  • the hydrogel has one or more or all of the following characteristics: is transparent, odorless, colorless, has a viscosity (at 25 °C) of, e.g., 2,000-10,000 cP, 2,000-8,000 cP, or 6,000-10,000 cP (measured using, for example, a rheometer), has assay and dose uniformity (which can be measured by, e.g ., flame photometry or atomic adsorption spectrometry (AAS)), has an emollient "smooth-feel" texture, could be easily applied to skin, readily spreads over a surface, has minimal migration to surrounding sites, has minimal run off, has a neutral pH (e.g., pH 6.5-7.5), is sterile, is stable for an extended period ( e.g., 1 week or more, 2 weeks or
  • the hydrogel is stable at room temperature for up to 4 weeks or more. In one embodiment, the hydrogel is stable at room temperature for up to 8 weeks or more. In one embodiment, the hydrogel is stable at 4 °C for up to 6 months or more. In one embodiment, the hydrogel is stable at 4 °C for up to 1 year or more.
  • a hydrogel is prepared with the excipients and an amount of active ingredient chosen to contribute to one or more of the foregoing or following attributes, which may be desirable for a topical formulation for use in the methods described herein: viscosity (e.g., imparted by carboxymethyl cellulose), surface wetting ability and prevention of "dry-out” (e.g., imparted by glycerol), preservative effectiveness (e.g., imparted by parabens, such as methyl or propyl parabens, although in certain embodiments, a paraben-free formulation may also be generated), maintenance of pH, stability ( e.g ., imparted by altering the strength of surfactants used in the hydrogel) and pharmacokinetic properties (such as rate of release of active ingredient from the formulation, and peak and trough concentrations of active ingredient in skin and blood).
  • viscosity e.g., imparted by carboxymethyl cellulose
  • surface wetting ability and prevention of "dry-out”
  • excipients that are wound compatible, contribute to sterility, wound healing, and/or aid in cell attachment and/or proliferation may be included, such as, e.g ., allantoin or sodium alginate.
  • the hydrogel is formulated so that it releases active ingredients, where present, at varying rates. Release rate may be modified by one or more of the following: incorporating the formulation into different scaffolds, such as described in Section 5.5.5 infra, modifying the concentration of components, including any active ingredients, of the formulation, or modifying the types and concentrations of excipients. In some embodiments, most or all of the active ingredient is released from the formulation within 2 hours, within 4 hours, within 8 hours, within 10 hours, within 12 hours, within 16 hours, within 24 hours, within 36 hours, within 48 hours, within 3 days, within 5 days, within 7 days, within 10 days, within 14 days, within 30 days, or within 2 months or more.
  • the formulation is an "immediate release” formulation, i.e., releases 90-100% of active ingredient within the first day of administration.
  • the formulation is an "Intermediate Release” formulation, i.e., releases 90-100% of active ingredient within 1 to 3 days of administration.
  • the formulation is a "Sustained Release” formulation, i.e., releases 90-100% of active ingredient within 3 to 7 days of administration.
  • the post-perturbation composition formulated for topical administration is in the form of an emulsion, e.g ., a cream.
  • the cream is an oil/water emulsion.
  • a cream contains approximately 75%, 80%, 85%, 90%, or 95% water.
  • the cream e.g ., dispersion, suspension, colloid or emulsion
  • the cream is stable at room temperature for up to 4 weeks or more. In one embodiment, the cream is stable at room temperature for up to 8 weeks or more. In one embodiment, the cream is stable at 4 °C for up to 6 months or more. In one embodiment, the cream is stable at 4 °C for up to 1 year or more.
  • a cream is prepared with the excipients and an amount of active ingredient chosen to contribute to one or more of the foregoing or following attributes, which may be desirable for a topical formulation for use in the methods described herein: viscosity, surface wetting ability and prevention of "dry-out,” preservative effectiveness, maintenance of pH, stability (e.g.
  • excipients that are wound compatible, contribute to wound healing, and/or aid in cell attachment and/or proliferation may be included, such as, e.g ., allantoin or sodium alginate.
  • the rate of release of active ingredients, where present, from the cream may be modified by one or more of the following: incorporating the formulation into different scaffolds, such as described in Section 5.5.5 infra, modifying the concentration of active ingredients in the formulation, or modifying the types and concentrations of excipients.
  • the rate of release of active ingredients from the cream may be decreased by decreasing the concentration of hydrophilic polymers in the cream.
  • the rate of release of active ingredients from the cream may be altered by varying the concentration of cetearyl alcohol, lanolin alcohol, or by varying the types of aqueous or non-aqueous carrier(s), and preferably non-aqueous carrier(s) (e.g ., silicone, mineral oil, petrolatum, etc .), used.
  • aqueous or non-aqueous carrier(s) e.g ., silicone, mineral oil, petrolatum, etc .
  • most or all of the active ingredient is released from the formulation within 2 hours, within 4 hours, within 8 hours, within 10 hours, within 12 hours, within 16 hours, within 24 hours, within 36 hours, within 48 hours, within 3 days, within 5 days, within 7 days, within 10 days, within 14 days, within 30 days, or within 2 months or more.
  • most or all of the active ingredient is released from a cream described herein within 10 hours.
  • all of the active ingredient is released from the cream within 10 hours.
  • most or all of the active ingredient is released from a cream described herein within 24 hours.
  • the formulation is an "immediate release" formulation, i.e., releases 90-100% of active ingredient within the first day of administration.
  • the formulation is an "Intermediate Release” formulation, i.e., releases 90-100% of active ingredient within 1 to 3 days of administration. In another embodiment, the formulation is a "Sustained Release” formulation, i.e., releases 90-100% of active ingredient within 3 to 7 days of administration.
  • the cream is an immediate release formulation.
  • a formulation may be generated using a two-phase system: (i) an aqueous phase for dissolving any active ingredients and hydrophilic excipients and (ii) a non-aqueous phase for dissolving hydrophobic polymers.
  • the cream is a water-in-oil emulsion, which acts not only act as a biocompatible skin emollient, but also as a delivery system for any active ingredients.
  • the cream is an intermediate release formulation.
  • the intermediate release cream formulation is an emulsion prepared by homogenization of two phases, as described, e.g ., for the immediate release cream formulation above.
  • the cream is a sustained release formulation.
  • the sustained release cream formulation is prepared by homogenization of two phases (an aqueous phase and a non-aqueous phase), as described, e.g. , for the immediate and intermediate release cream formulations above, but by decreasing the concentration of hydrophilic polymers in the non-aqueous phase.
  • a 50 kg patient is administered a single droplet of a hydrogel described herein at 3 sites, twice daily.
  • the hydrogel is administered once daily.
  • the hydrogel is administered twice daily.
  • doses are administered 6 hours apart, or 7 hours apart, or 8 hours apart, or 9 hours apart, or 10 hours apart, or 11 hours apart, or 12 hours apart. In a particular embodiment, the doses are administered 7 to 8 hours apart.
  • Most drugs for hair loss aim to retain the existing hair follicles in their active cycling states, or to rejuvenate telogen hair follicles to actively cycling anagen states.
  • Other drugs encourage the conversion of vellus hair to terminal hair.
  • an integumental perturbation treatment that may encourage the growth of "new" hair follicles or activation of existing follicles
  • a drug treatment that may retain hair follicles in their actively cycling states
  • Such treatments may be more effective, efficient, cost-effective, and user friendly. For example, fewer treatments may be required.
  • the hair that results may be more cosmetically satisfactory, longer lasting, thicker, more uniform, longer, and properly pigmented hair. Such characteristics are associated with terminal hair rather than vellus hair.
  • integumental perturbation methods described in Section 5.1 supra may be used in combination treatments with hair growth-promoting agents, and optionally in combination with the treatments described in Section 5.4 below.
  • a hair growth-promoting agent described herein promotes hair follicle development and growth, resulting in the transition of vellus hair on an area of the skin to nonvellus, e.g ., intermediate or terminal, hair.
  • a hair growth-promoting agent described herein acts synergistically with the integumental perturbation method to promote hair growth.
  • the effect that each treatment offers could be an additive or synergistic improvement, or a combination of two different biologically defined effects, to achieve the desired end result.
  • the hair growth-promoting agent is a treatment that promotes hair growth and/or treats a disease or condition associated with excessive hair loss. Any treatment that promotes hair growth and/or treats a disease or condition associated with excessive hair loss that is known in the art or yet to be developed is contemplated for use in accordance with these embodiments.
  • the hair growth-promoting agent treatment comprises treatment with one or more channel openers (e.g., potassium channel opener, e.g ., an ATP-sensitive potassium channel (K ATP opener), or an activator of such a channel), such as, e.g., minoxidil (e.g., marketed as Rogaine or Regaine), diazoxide, or phenytoin.
  • the hair growth-promoting agent treatment comprises treatment with minoxidil.
  • channel openers e.g., potassium channel opener, e.g ., an ATP-sensitive potassium channel (K ATP opener), or an activator of such a channel
  • minoxidil e.g., marketed as Rogaine or Regaine
  • diazoxide e.g., phenytoin
  • the hair growth-promoting agent treatment comprises treatment with minoxidil.
  • Commonly used dosage forms of minoxidil that may be used in accordance with these embodiments are topical solutions comprising 2% minoxidil or 5% minoxidil, for example,
  • the hair growth-promoting agent treatment comprises treatment with one or more 5 ⁇ -reductase inhibitors.
  • 5 ⁇ -reductase inhibitors include finasteride, dutasteride ( e.g ., Avodart), turosteride, bexlosteride, izonsteride, epristeride, epigallocatechin, MK-386, azelaic acid, FCE 28260, and SKF 105,111.
  • Commonly used dosage forms of finasteride that may be used in such treatments are, for example, oral finasteride at 1 mg/day.
  • the hair growth-promoting agent treatment comprises treatment with one or more antiandrogens, such as, e.g., finasteride (e.g., marketed as Propecia or Proscar), ketoconazole, fluconazole, spironolactone, flutamide, diazoxide, 17-alpha-hydroxyprogesterone, 11-alpha-hydroxyprogesterone, ketoconazole, RU58841 , dutasteride (marketed as Avodart), fluridil, or QLT-7704, an antiandrogen oligonucleotide, or others described in Poulos & Mirmirani, 2005, Expert Opin. Investig. Drugs 14:177-184 , the contents of which is incorporated herein by reference.
  • finasteride e.g., marketed as Propecia or Proscar
  • ketoconazole e.g., marketed as Propecia or Proscar
  • ketoconazole e.g., marketed as Propecia
  • the hair growth-promoting agent treatment comprises treatment with one or more prostaglandin F2 ⁇ analogs, prostaglandin analogs, or prostaglandins.
  • prostaglandin F2 ⁇ analogs include bimatoprost (e.g., Latisse, Lumigan), latanoprost (trade name Xalatan), travoprost (trade name Travatan), tafluprost, unoprostone, dinoprost (trade name Prostin F2 Alpha), AS604872, BOL303259X, PF3187207, carboprost (trade name Hemabate).
  • prostaglandin F2 ⁇ analogs for use in accordance with the methods described herein, see, e.g., US Patent Nos. 8,017,655 , 5,688,819 , 6,403,649 , 5,510,383 , 5,631,287 , 5,849,792 , 5,889,052 , 6,011,062 , 7,163,959 , 5,296,504 , 5,422,368 , 6,429,226 , and 6,946,120 , the entire contents of each of which is incorporated herein by reference in its entirety. See also, with respect to latanoprost, Uno et al., 2002, Acta Derm Venereol 82:7-12 , the contents of which is incorporated herein by reference in its entirety.
  • the hair growth-promoting agent treatment comprises treatment with one or more of the following hair growth-promoting agents: kopexil (for example, the product KeraniqueTM), CaCl 2 , botilinum toxin A, adenosine, ketoconazole, DoxoRx, Docetaxel, FK506, GP11046, GP11511, LGD 1331, ICX-TRC, MTS-01, NEOSH101, HYG-102440, HYG-410, HYG-420, HYG-430, HYG-440, spironolactone, CB-03-01, RK-023, Abatacept, Viviscal®, MorrF, ASC-J9, NP-619, AS101, Metron-F-1, PSK 3841, Targretin ( e.g ., 1% gel), MedinGel, PF3187207, BOL303259X, AS604872, THG11331, PF-277343
  • the hair growth-promoting agent treatment comprises treatment with one or more of the following: herbs (such as, e.g., saw palmetto, glycine soja, Panax ginseng, Castanea Sativa, Arnica Montana, Hedera Helix Geranium Maculatum), triamcinolone acetonide (e.g ., suspension of 2.5 to 5 mg/ml for injection), a topical irritant (e.g. , anthralin) or sensitizer ( e.g ., squaric acid dibutyl ester [SADBE] or diphenyl cyclopropenone [DPCP]), clomipramine, unsaturated fatty acids (e.g.
  • herbs such as, e.g., saw palmetto, glycine soja, Panax ginseng, Castanea Sativa, Arnica Montana, Hedera Helix Geranium Maculatum
  • triamcinolone acetonide e.g
  • the hair growth-promoting agent treatment comprises treatment with nitroxide spin labels (e.g. , TEMPO and TEMPOL). See United States Patent 5,714,482 , which is incorporated herein by reference.
  • the hair growth-promoting agent treatment comprises treatment with an androgen receptor inhibitor, which have been shown to be useful for stimulating scalp hair growth ( Hu LY, et al., 2007, Bioorg Med Chem Lett. 2007 17:5983-5988 ).
  • the hair growth-promoting agent treatment comprises treatment with a copper peptide(s), preferably applied topically, or another compound with superoxide dismutation activity.
  • the hair growth-promoting agent treatment comprises treatment with an agent that increases nitric oxide production (e.g. , arginine, citrulline, nitroglycerin, amyl nitrite, or sildenafil (Viagra)).
  • an agent that increases nitric oxide production e.g. , arginine, citrulline, nitroglycerin, amyl nitrite, or sildenafil (Viagra)
  • such compounds are administered further in combination with a catalase or catalase mimetic, or other antioxidant or free radical scavenger.
  • the hair growth-promoting agent treatment comprises treatment with a compound that mobilizes bone marrow-derived stem cells (e.g ., growth factors such as G-CSF and/or chemical agents such as plerixafor (Mozobil®)); and/or that regulates the differentiation of these stem cells into gender-specific specialized human hair follicles (e.g ., using agents such as finasteride, fluconazole, spironolactone, flutamide, diazoxide, 11-alpha-hydroxyprogesterone, ketoconazole, RU58841 , dutasteride, fluridil, or QLT-7704, an antiandrogen oligonucleotide, cyoctol, topical progesterone, topical estrogen, cyproterone acetate, ru58841, combination 5 ⁇ -reductase inhibitors, oral contraceptive pills, and others in Poulos & Mirmirani, 2005, Expert Opin.
  • Investig. Drugs 14:177-184 incorporated herein by reference, or any other antiestrogen, an estrogen, or estrogen-like drug (alone or in combination with agents that increase stem cell plasticity; e.g ., such as valproate), etc., known in the art), that can result in, e.g., the appearance of specialized follicles having features that are different from natural follicles in the target location of skin.
  • the hair growth-promoting agent treatment comprises treatment with one or more agents that counteract age-related hair thinning and/or hair follicle cell senescence (also referred to herein as "anti-senescence agents") for example, antioxidants such as glutathione, ascorbic acid, tocopherol, uric acid, or polyphenol antioxidants); inhibitors of reactive oxygen species (ROS) generation, such as superoxide dismutase inhibitors; stimulators of RO5 breakdown, such as selenium; mTOR inhibitors, such as rapamycin; or sirtuins or activators thereof, such as resveratrol, or other SIRT1, SIRT3 activators, or nicotinamide inhibitors.
  • antioxidants such as glutathione, ascorbic acid, tocopherol, uric acid, or polyphenol antioxidants
  • ROS reactive oxygen species
  • stimulators of RO5 breakdown such as selenium
  • mTOR inhibitors such as rapamycin
  • the hair growth-promoting agent treatment comprises treatment with one or more agents that induce an immune response or cause inflammation, such as, e.g ., tetanus toxoid, topical non-specific irritants (anthralin), or sensitizers (squaric acid dibutyl ester [SADBE] and diphenyl cyclopropenone [DPCP]). While not intending to be bound by any theory, it is thought that by contacting these agents to the skin, lymphocytes and hair follicle stem cells may be recruited to skin.
  • the hair growth-promoting agent treatment comprises treatment with a chemical or mechanical (such as those discussed infra ) treatment that induces an inflammatory process in the skin. While not intending to be bound by any theory, inducing inflammation in the site where hair growth is desired helps to recruit stem cells to the tissues that drive the formation of new follicles.
  • the hair growth-promoting agent treatment comprises treatment with an antiapoptotic compound.
  • the antiapoptotic compound is not a Wnt or a Wnt agonist.
  • the hair growth-promoting agent treatment comprises treatment with stem cell therapy, hair cloning, hair transplantation, scalp massage, a skin graft, hair plugs, follicular unit extraction, or any surgical procedure aimed at hair restoration.
  • a hair growth-promoting agent described herein may be used at a dosage or in a range of dosages known in the art for that agent (e.g. , as made available on a package insert or in the Physicians' Desk Reference).
  • the regular dosage of the hair growth-promoting agent is adjusted to optimize a combination treatment (e.g ., integumental perturbation or treatment with another active ingredient) described herein.
  • the regular dosage may be increased or decreased as directed by the physician.
  • a lower dosage may be used over a shorter duration owing to the synergistic effect of combination with another treatment described herein.
  • the hair growth-promoting agent may be used in its commercially available form.
  • the form of the hair growth-promoting agent is adjusted to optimize a combination treatment (e.g ., integumental perturbation or treatment with another active ingredient) described herein.
  • the hair growth-promoting agent is formulated as a different salt form than that which is commercially available.
  • the hair growth-promoting agent is formulated for topical administration, e.g ., by incorporation into a pharmaceutical composition for post-perturbation treatment described in Section 5.2 infra.
  • the hair growth-promoting agent enhances conversion of vellus hair to nonvellus hair. In a particular embodiment, the hair growth-promoting agent enhances conversion of vellus hair to terminal hair.
  • Exemplary hair growth-promoting agents that promote conversion of vellus to nonvellus hair that may be used in accordance with these embodiments are prostaglandin F2 ⁇ analogs (in one aspect, latanoprost), minoxidil, etc.
  • the hair growth-promoting agent enhances conversion of telogen hair to anagen hair.
  • the hair growth-promoting agent enhances conversion of telogen hair to anagen hair.
  • Exemplary hair growth-promoting agents that promote conversion of telogen to anagen hair that may be used in accordance with these embodiments are prostaglandin F2 ⁇ analogs (in one aspect, latanoprost), minoxidil, etc.
  • the hair growth-promoting agent treatment comprises treatment with an antiandrogen (e.g., a 5 ⁇ -reductase inhibitor) and a channel opener (e.g ., minoxidil).
  • an antiandrogen e.g., a 5 ⁇ -reductase inhibitor
  • a channel opener e.g ., minoxidil
  • a 5 ⁇ -reductase inhibitor is administered in combination with minoxidil.
  • finasteride is administered in combination with minoxidil.
  • the hair growth-promoting agent treatment comprises treatment with a prostaglandin F2 ⁇ or prostamide analog (e.g., latanoprost, bimatoprost, etc .) in combination with a channel opener (e.g. , minoxidil).
  • a prostaglandin F2 ⁇ or prostamide analog is administered in combination with minoxidil.
  • latanoprost is administered in combination with minoxidil.
  • bimatoprost is administered in combination with minoxidil.
  • a treatment described herein for promoting hair growth in a female subject does not comprise finasteride or ketoconazole. In some embodiments, a treatment described herein for promoting hair growth in a pregnant female subject is not finasteride or ketoconazole.
  • a treatment described herein for promoting hair growth does not comprise minoxidil. In some embodiments a treatment described herein for promoting hair growth does not comprise finasteride. In some embodiments a treatment described herein for promoting hair growth does not comprise dutasteride. In some embodiments a treatment described herein for promoting hair growth does not comprise fluridil. In some embodiments a treatment described herein for promoting hair growth does not comprise spironolactone. In some embodiments a treatment described herein for promoting hair growth does not comprise cyproterone acetate. In some embodiments a treatment described herein for promoting hair growth does not comprise bicalutamide. In some embodiments a treatment described herein for promoting hair growth does not comprise flutamide.
  • a treatment described herein for promoting hair growth does not comprise nilutamide. In some embodiments a treatment described herein for promoting hair growth does not comprise an inhibitor of an androgen receptor. In some embodiments a treatment described herein for promoting hair growth does not comprise an androgen antagonist. In some embodiments a treatment described herein for promoting hair growth does not comprise an anti-androgen.
  • the hair growth-promoting agent or formulation thereof can be administered topically, subcutaneously, intravenously, orally, etc. Regardless of the route of administration used for hair growth-promoting agent delivery, the dosing regimen should be adjusted so that maximum benefit is achieved while reducing potential side effects.
  • the target concentration of hair growth-promoting agent should be maintained in the skin or blood, and preferably the skin, for at least 1 day; at least 2 days; at least 3 days; at least 4 days; at least 5 days; at least 6 days; at least 7 days; at least 8 days; at least 9 days; at least 10 days; at least 11 days; at least 12 days; at least 13 days; at least 14 days; at least 15 days; at least 16 days; at least 19 days; or at least 21 days; and, in certain embodiments, not more than 28 days.
  • the target concentration of hair growth-promoting agent is maintained in skin or blood, and preferably the skin, for 1 month or more, 2 months or more, 3 months or more, 3 to 6 months or more, or 6 to 12 months or more.
  • a modified release form can be used to achieve the target concentration of hair growth-promoting agent for shorter maintenance periods (i.e., for at least 1, 2 or 3 days). Maintenance periods longer than 3 days may require repeated application of the hair growth-promoting agent treatments. In some embodiments, it is preferable to allow the concentration of hair growth-promoting agent to decline between dosages.
  • topical administration of a hair growth-promoting agent is preferred over oral or subcutaneous administration.
  • a topically administered hair growth-promoting agent may achieve a higher concentration of hair growth-promoting agent in skin than in the blood, thereby reducing the risk of toxicity that may be associated with elevated blood levels of hair growth-promoting agent.
  • a subcutaneously or orally administered hair growth-promoting agent may be preferred in order to achieve a controlled release of hair growth-promoting agent from the blood to the skin.
  • a dosage should be chosen that maximizes efficacy while minimizing toxicity. Such a dosage may be chosen using the assays described in Section 5.3. Patients should be monitored for toxic side effects according to standard clinical practice.
  • hair growth-promoting agent doses should be adjusted on the basis of the blood concentration (serum or plasma) drawn (by convention) 12 or 24 hours after the last dose of the hair growth-promoting agent.
  • an effective amount of hair growth-promoting agent is administered such that the target concentration of hair growth-promoting agent in plasma or serum, as measured 30 minutes to 1 hour after the hair growth-promoting agent treatment, is less than 0.1 nM, 0.1-1.0 nM, 1.0-10 nM, 10-50 nM, 50-100 nM, 100-500 nM, 0.5-1.0 ⁇ M, 1.0 ⁇ M-2.0 ⁇ M, 2.0-2.5 ⁇ M, 2.5-3.0 ⁇ M, or 3.0 ⁇ M or greater.
  • an effective amount of hair growth-promoting agent is administered such that the plasma or serum hair growth-promoting agent concentration measured either 8 hours, 16 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month after the hair growth-promoting agent treatment is less than 0.1 nM, 0.1 to 1 nM, 0.5 to 1.5 nM, 1 to 10 nM, 10 to 50 nM, 50 to 100 nM, 100 to 150 nM, 150 to 200 nM, 250 to 300 nM, 100 to 250 nM, 100 to 500 nM, 200 to 400 nM, 500 to 1000 nM; or 1000 to less than 100000 nM.
  • the plasma or serum hair growth-promoting agent concentration reaches at least 1 nM.
  • the peak plasma level never reaches greater than 1 ⁇ M.
  • Serum hair growth-promoting agent concentration may be measured using methods of liquid chromatography and/or mass spectrometry, which are well known in the art.
  • an amount of hair growth-promoting agent is administered such that the target concentration of hair growth-promoting agent in the skin is 0.1 nM to 1 nM, 1 nM to 10 nM, 10-100 nM, 100-500 nM, 500-1000 nM, 1 to 1.5 ⁇ M, 1 to 2.5 ⁇ M, 1 to 5 ⁇ M, 5 to 10 ⁇ M, 10 to 50 ⁇ M, 50 to 100 ⁇ M, 100 to 150 ⁇ M, 150 to 200 ⁇ M, 250 to 300 ⁇ M, 100 to 250 ⁇ M, 100 to 500 ⁇ M, 200 to 400 ⁇ M, 500 to 1000 ⁇ M, 1 to 10 mM, 10 to 100 mM, 100 to 200 mM, or 500 to 1000 mM.
  • the concentration of hair growth-promoting agent achieved in the skin is greater than 0.1 nM. In some embodiments, the concentration of hair growth-promoting agent achieved in the skin is greater than 1 nM. In some embodiments, the concentration of hair growth-promoting agent achieved in the skin is greater than 100 nM. In some embodiments, the concentration of hair growth-promoting agent achieved in the skin is greater than 500 nM. In one embodiment, the concentration of hair growth-promoting agent achieved in the skin is approximately 10-100 nM. In one embodiment, the concentration of hair growth-promoting agent achieved in the skin is approximately 100-1000 nM. In one embodiment, the concentration of hair growth-promoting agent achieved in the skin is approximately 1 ⁇ m to 10 ⁇ m.
  • the concentration of hair growth-promoting agent achieved in the skin is approximately 10-100 ⁇ m.
  • an amount of hair growth-promoting agent is administered such that the concentration of hair growth-promoting agent delivered to the skin is 0.0000001 mg/ml to 0.000001 mg/ml, 0.000001 mg/ml to 0.00001 mg/ml, 0.00001 mg/ml to 0.0001 mg/ml, 0.0001 mg/ml to 0.001 mg/ml, 0.001 mg/ml to 0.01 mg/ml, 0.01 mg/ml to 0.1 mg/ml, 0.1 mg/ml to 1 mg/ml, I mg/ml to 10 mg/ml.
  • the concentration of hair growth-promoting agent delivered to the stratum corneum is 0.0000001 mg/ml to 0.000001 mg/ml, 0.000001 mg/ml to 0.00001 mg/ml, 0.00001 mg/ml to 0.0001 mg/ml, 0.0001 mg/ml to 0.001 mg/ml, 0.001 mg/ml to 0.01 mg/ml, 0.01 mg/ml to 0.1 mg/ml, 0.1 mg/ml to 1 mg/ml, 1 mg/ml to 10 mg/ml.
  • One of skill in the art would be able to measure hair growth-promoting agent concentrations in skin using techniques known in the art, for example, mass spectroscopy, e.g ., inductively coupled plasma mass spectroscopy (ICP-MS), of the LC/MS/MS assay used herein.
  • mass spectroscopy e.g ., inductively coupled plasma mass spectroscopy (ICP-MS)
  • ICP-MS inductively coupled plasma mass spectroscopy
  • the hair growth-promoting agent concentration is measured in the hair shaft using techniques known in the art, e.g., Tsanaclis & Wicks, 2007, Forensic Science Intl. 176: 19-22 , which is incorporated by reference herein in its entirety.
  • the hair growth-promoting agent can be applied topically, e.g., as a cream, gel, ointment, suspension, or other form for topical administration as described in Section 5.3 supra.
  • the hair growth-promoting agent can be formulated as a pharmaceutical composition for topical administration.
  • topical hair growth-promoting agent is administered twice daily. In some embodiments, topical hair growth-promoting agent is administered once daily.
  • the form of the hair growth-promoting agent for topical administration (e.g., gel, cream, ointment, salve, etc.) comprises, w/w, 0.000001%, 0.00001%, 0.0001% hair growth-promoting agent, 0.001% hair growth-promoting agent, 0.01% hair growth-promoting agent, 0.1% hair growth-promoting agent, 0.5% hair growth-promoting agent, 1 % hair growth-promoting agent, and 10% hair growth-promoting agent.
  • the form of the hair growth-promoting agent for topical administration comprises, w/w, 0.000001% to 0.00001% hair growth-promoting agent, 0.00001% to 0.0001% hair growth-promoting agent, 0.0001% to 0.001% hair growth-promoting agent, 0.001% to 0.01% hair growth-promoting agent, 0.01% to 0.1% hair growth-promoting agent, 0.1% to 1.0% hair growth-promoting agent, 1.0% to 5% hair growth-promoting agent, 5% to 10% hair growth-promoting agent, or 10% to 15% hair growth-promoting agent.
  • the form of the hair growth-promoting agent for topical administration is 0.00001% to 1.0% w/w hair growth-promoting agent.
  • a topical formulation is formulated such that 0.01 mg hair growth-promoting agent per kg of patient weight (mg/kg) is administered, or 0.02 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2 mg/kg, 5.0 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg, 650 mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg, 1000 mg/kg, or 1500 mg/kg is administered.
  • the topical formulation contains a dose in the range of about 0.01 mg/kg to about 0.1 mg/kg, 0.02 mg/kg to about 0.2 mg/kg, 0.1 mg/kg to about 1 mg/kg, 0.2 mg/kg to about 2 mg/kg, 0.01 mg/kg to about 2 mg/kg, 0.1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 20 mg/kg, about 2 mg/kg to about 10 mg/kg, about 100 mg/kg to about 1 g/kg, about 125 mg/kg to about 500 mg/kg, or about 150 mg/kg to about 300 mg/kg of hair growth-promoting agent.
  • the topical formulation contains a dose in the range of about 0.01 mg/kg to about 1 mg/kg.
  • the topical formulation contains a dose in the range of about 0.02 mg/kg to about 2 mg/kg.
  • the concentration of hair growth-promoting agent in a particular topical formulation to deliver the intended dose of hair growth-promoting agent will depend on the release properties of the hair growth-promoting agent, the hydrophobicity of the hair growth-promoting agent, the partition coefficient of the hair growth-promoting agent, etc.
  • the amount of hair growth-promoting agent to generate a topical formulation with one of the aforementioned concentrations of hair growth-promoting agent is readily deducible by one of ordinary skill in the art, and depends upon several factors including, e.g., its salt form, stability, release properties, its hydrophobicity or hydrophilicity, etc.
  • Most drugs for hair loss aim to retain the existing hair follicles in their active cycling states, or to rejuvenate telogen hair follicles to actively cycling anagen states.
  • Other drugs encourage the conversion of vellus hair to terminal hair.
  • a treatment that encourages the growth of new hair follicles and/or growth of vellus hair toward terminal hair (such as integumental perturbation) combined with one that retains the hair follicles in their actively cycling states or promotes conversion of vellus to nonvellus hair, or maintains new terminal hairs or enhances further growth of new terminal hairs, offers significant value to the individual who is balding.
  • the combined modality of treatment could involve alternating treatment of each dosage form or concurrent or simultaneous treatment.
  • integumental perturbation in the affected skin tissue can stimulate, activate, or reorganize pre-existing hair follicles, such that resident hair follicles may be reprogrammed. Accordingly, and without being bound by any theory for how the invention works, integumental perturbation in combination with one or more hair growth-promoting agents provides an environment for hair growth and follicles with desired properties.
  • New hair follicles originate from Hair Follicle Stem Cells (FSCs), oligopotent cells whose progeny can differentiate into the highly differentiated specialized cells of the hair follicle (see Amoh Y, et al. Human hair follicle pluripotent stem (hfPS) cells promote regeneration of peripheral-nerve injury: an advantageous alternative to ES and iPS cells. J Cell Biochem, 2009, 107:1016-1020 ; and Amoh Y, et al. Nascent blood vessels in the skin arise from nestin-expressing hair-follicle cells. Proc Natl Acad Sci USA. 2004 Sep 7;101(36):13291-5 . Epub 2004 Aug 26). ).
  • FSCs Hair Follicle Stem Cells
  • hfPS Human hair follicle pluripotent stem
  • a dermal stem cell population has been identified for hair follicles in mouse (see Biernaskie J, Paris M, Morozova O, et al. SKPs derive from hair follicle precursors and exhibit properties of adult dermal stem cells. Cell Stem Cell. 2009;5(6):610-623 ).
  • FSCs originate from one or more of the following: (i) existing follicles ("follicle derived follicle stem cells” or “FDFSC”) (see, e.g., Toscani et al., 2009, Dermatol Surg.
  • FDFSC follicle derived follicle stem cells
  • TDFSC tissue derived follicle stem cells
  • BMDFSC bone marrow derived follicle stem cells
  • FSCs generate new hair follicles that preserve the type of hair follicle that is typical for each location of skin or scalp. For example, FSCs from the coronal scalp of a male with MPHL typically generate atrophic follicles with vellus or club hairs. In contrast, FSCs from the occipital scalp of the same male typically generate follicles with terminal hair that are not subject to involution in response to DHT.
  • FSCs responsible for follicle formation may be reprogrammed.
  • FSCs in the process of asymmetric division and subsequent differentiation are susceptible to signals (such as estrogen or testosterone) that alter their differentiation program.
  • signals such as estrogen or testosterone
  • FSCs from the coronal scalp of a male with MPHL under the influence of estrogen, can generate follicles with terminal hair that are not subject to involution in response to DHT.
  • Such follicles have characteristics usually associated with: (i) pre-alopecia follicles in the coronal scalp; (ii) female-type follicles on the coronal scalp; or (iii) occipital scalp type follicles.
  • antagonizing estrogen or testosterone the assumption of the default hair pattern in a particular skin area may be prevented.
  • a female's unwanted moustache hair may be reduced by perturbing the skin of the upper lip and administering a testosterone antagonist.
  • treatment with one or more hair growth-promoting agents in combination with integumental perturbation provides a window during which a third treatment that alters the follicle development program may be administered in order to significantly change the number or quality of follicles in a particular area of skin.
  • the third treatment e.g ., estrogen or testosterone modulator, such as those described in Poulos & Mirmirani, 2005, Expert Opin. Investig. Drugs 14:177-184 (incorporated herein by reference
  • the third treatment is administered after integumental perturbation.
  • the third treatment is administered 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, or 2 weeks after integumental perturbation. In one embodiment, the third treatment is administered at the time of integumental perturbation and then daily for 5 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, the third treatment is administered daily for 5 days beginning as soon as the scab falls off. In some embodiments, the third treatment is administered in order to modulate the neoepidermis that forms underneath the scab. In some such embodiments, the third treatment is administered at the time of integumental perturbation and up to some time after scab falls off, for example, between 5 - 14 days following integumental perturbation.
  • the course of treatment with the third treatment is short, for example, limited to a few days just following scab detachment, or even continued only for as long as the scab is still attached.
  • the timing of the integumental perturbation, hair growth-promoting agent administration, and the third treatment can be monitored and adjusted so that optimal results are achieved.
  • a method of the invention comprising integumental perturbation (Section 5.1) and/or post-perturbation treatment (Section 5.2) and/or administration of a pharmaceutical composition comprising one or more hair growth-promoting agents (Section 5.3) may be combined with one or more additional treatments with an active ingredient.
  • the one or more additional treatments with an active ingredient can be administered before, during, or after one or more of the steps of integumental perturbation, post-perturbation treatment, and/or administration of a hair growth-promoting agent.
  • the active ingredient is administered together with, optionally in the same formulation, a post-perturbation pharmaceutical composition.
  • the active ingredient is administered together with, optionally in the same formulation, a hair growth-promoting agent.
  • an active ingredient for formulation into a pharmaceutical composition for an additional treatment can be selected from, e.g., cell therapy (such as a stem cell), a formulation for gene therapy (such as, e.g., a virus, virus-like particle, virosome), an antibody or antigen-binding fragment thereof, an herb, a vitamin (e.g., a form of vitamin E, a vitamin A derivative, such as, e.g ., all-trans retinoic acid (ATRA), a B vitamin, such as, e.g., inositol, panthenol, or biotin, or a vitamin D3 analog), a mineral, essential oils, an antioxidant or free radical scavenger, amino acids or amino acid derivatives, a shampoo ingredient (e.g., caffeine, ammonium chloride, ammonium lauryl sulfate, glycol, sodium laureth sulfate, sodium lauryl sulfate, ketoconazole,
  • a shampoo ingredient
  • carboxyalkylates of branched alcohols and/or alkoxylates thereof e.g ., tridecyl carboxy alkylates, cerulenin or a cerulenin analog, including pharmaceutically acceptable salts or solvates thereof, another fatty acid synthase inhibitor, such as triclosan or analogs thereof, a polyphenol extracted from green tea (EGCG), available from Sigma Corporation (St.
  • EGCG green tea
  • a massage agent e.g., a massage agent, an exfoliant, an anti-itch agent, a pro-inflammatory agent, an immunostimulant (e.g., cytokines, agonists or antagonists of various ligands, receptors and signal transduction molecules of the immune system, immunostimulatory nucleic acids, an adjuvant that stimulates the immune response and/or which causes a depot effect), a cell cycle regulator, a hormonal agonist, hormonal antagonist (e.g.
  • a steroid e.g., dexamethasone, retinoids, deltoids, betamethasone, cortisol, cortisone, prednisone, dehydrotestosterone, glucocorticoids, mineralocorticoids, estrogen, testosterone, progestins
  • antigestagens e.g.
  • an antiandrogen e.g., cyproterone acetate
  • an antiestrogen e.g., mepyramine, diphenhydramine, and antazoline
  • an anti-inflammatory e.g. , corticosteroids, NTHEs, and COX-2 inhibitors
  • a retinoid e.g. , 13-cis-retinoic acid, adapalene, all-trans-retinoic acid, and etretinate
  • an immunosuppressant e.g.
  • cyclosporine tacrolimus, rapamycin, everolimus, and pimecrolimus
  • an antibiotic such as, e.g ., fluorouracil (5-FU or f5U) or other pyrimidine analogs, methotrexate, cyclophosphamide, vincristine
  • a mood stabilizer e.g ., valproic acid or carbamazepine
  • an antimetabolite e.g ., benzyl benzoate, benzalkonium chloride, benzoic acid, benzyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, camphorated metacresol, camphorated phenol, hexylresorcinol, methylbenzethonium chloride, cetrimide, chlorhexidine, chlorobutanol, chlorocresol,
  • the drug of choice is Minoxidil, Minoxidil sulfate, or another salt form such as chloride, carbonate, nitrate, etc.
  • the drug of choice is a prostaglandin, or a prostaglandin analogue, a prostaglandin prodrug.
  • the drug is a 5 alpha reductase inhibitor.
  • the drug will be formulated such it is targeted to a specific ligand present in the hair follicle.
  • the drug will be formulated into positively charged nanospheres, that will reside within the hair follicle as drug-containing depots.
  • the additional treatment comprises one or more antimicrobial agents or preservatives including, but not limited to, alkyl esters of p-hydroxybenzoic acid, hydantoins derivatives, propionate salts, phenols, cresols, mercurials, phenyoxyethanol, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), butyl, methyl- and propyl-parabens, sorbic acid, and any of a variety of quartemary ammonium compounds.
  • antimicrobial agents or preservatives including, but not limited to, alkyl esters of p-hydroxybenzoic acid, hydantoins derivatives, propionate salts, phenols, cresols, mercurials, phenyoxyethanol, benzyl alcohol, chlorobutanol, methyl and propyl
  • Suitable antioxidants include ascorbate, bisulfite and sodium metabisulfite.
  • the additional treatment comprises one or more anesthetic compounds.
  • Anesthetic compounds can be administered topically, by injection directly to the site of the disruption, or systemically.
  • Examples of anesthetic compounds for use in the methods and compositions described herein include lidocaine, prilocaine, bupivicaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, isoflurane, desflurane, sevoflurane, and nitrous oxide.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride, lidocaine and salts thereof, benzocaine and salts thereof and novacaine and salts thereof.
  • the additional treatment comprises one or more pain relievers, e.g., non-steroidal anti-inflammatory drugs or acetaminophen.
  • the additional treatment comprises one or more narcotic analgesics, selected from the group of, e.g ., alfentanil, benzylmorphine, codeine, codeine methyl bromide; codeine phosphate, codeine sulfate, desomorphine, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, ethylmorphine, hydrocodone, hydromorphone, methadone hydrochloride, morphine, morphine hydrochloride, morphine sulfate, nicomorphine, normethadone, normorphine, opium, oxycodone, oxymorphone, phenoperidine, and propiram.
  • the additional treatment comprises one or more non-narcotic analgesics, selected from the group of, e.g. , aceclofenac, acetaminophen, acetanilide, acetylsalicylsalicylic acid; aspirin, cubamazepine, dihydroxyaluminum acetylsalicylate, fenoprofen, fluproquazone, ibufenac, indomethacin, ketorolac, magnesium acetylsalicylate, morpholine salicylate, naproxen, phenacetin, phenyl salicylate, salacetamide, salicin, salicylamide, sodium salicylate, and tolfenamic acid.
  • Other pain treatments that may be used include nerve blocks or non-traditional pain medications, such as, e.g ., Lyrica (pregabalin) or Neurontin (gabapentin).
  • Soothing preparations may contain sodium bicarbonate (baking soda), and coal tar based products.
  • Formulations may also optionally contain a sunscreen or other skin protectant, or a waterproofing agent.
  • compositions described in Sections 5.2, 5.3, and 5.4 supra may be formulated with a pharmaceutically acceptable carrier (also referred to as a pharmaceutically acceptable excipients), i.e., a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, an encapsulating material, or a complexation agent.
  • a pharmaceutically acceptable carrier also referred to as a pharmaceutically acceptable excipients
  • each component is "pharmaceutically acceptable” in the sense of being chemically compatible with the other ingredients of a pharmaceutical formulation, and biocompatible, when in contact with the biological tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Suitable excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. For example, forms for topical administration such as a cream may contain excipients not suited for use in transdermal or intravenous administration. The suitability of a particular excipient depends on the specific active ingredients in the dosage form.
  • Exemplary, non-limiting, pharmaceutically acceptable carriers for use in the hair growth-promoting agent formulations described herein are the cosmetically acceptable vehicles provided in International Patent Application Publication No. WO 2005/120451 , which is incorporated herein by reference in its entirety.
  • compositions disclosed herein may be formulated to include an appropriate aqueous vehicle, including, but not limited to, water, saline, physiological saline or buffered saline (e.g ., phosphate buffered saline (PBS)), sodium chloride for injection, Ringers for injection, isotonic dextrose for injection, sterile water for injection, dextrose lactated Ringers for injection, sodium bicarbonate, or albumin for injection.
  • PBS phosphate buffered saline
  • Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, lanolin oil, lanolin alcohol, linoleic acid, linolenic acid and palm seed oil.
  • Suitable water-miscible vehicles include, but are not limited to, ethanol, wool alcohol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N -methyl-2-pyrrolidone (NMP), N , N- dimethylacetamide (DMA), and dimethyl sulfoxide (DMSO).
  • the water-miscible vehicle is not DMSO.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate, glutamate and citrate.
  • Suitable suspending and dispersing agents include but are not limited to sodium carboxymethylcelluose (CMC), hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP).
  • Suitable emulsifying agents include but are not limited to, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to, EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • a product for application to the scalp or face may additionally be formulated so that it has easy rinsing, minimal skin/eye irritation, no damage to existing hair, has a thick and/or creamy feel, pleasant fragrance, low toxicity, good biodegradability, and a slightly acidic pH (pH less than 7), since a basic environment weakens the hair by breaking the disulfide bonds in hair keratin.
  • compositions disclosed herein for example, the pharmaceutical compositions used in post-perturbation treatments described in Section 5.2, the hair growth-promoting agents described in Section 5.3, or the pharmaceutical agents described in Section 5.4, can be formulated in forms suitable for topical ( e.g. , applied directly to the skin, transdermal, or intradermal), subcutaneous, intramuscular, intravenous or by other parenteral means, oral administration, sublingual administration, or bucchal administration.
  • topical e.g. , applied directly to the skin, transdermal, or intradermal
  • subcutaneous, intramuscular, intravenous or by other parenteral means e.g., oral administration, sublingual administration, or bucchal administration.
  • the pharmaceutical compositions for use in the methods and uses disclosed herein can be administered in forms suitable for topical ( e.g.
  • the topical (e.g. , applied directly to the skin, transdermal, or intradermal) administration is accomplished with the use of a mechanical device, such as, e.g., an iontophoretic device.
  • a mechanical device such as, e.g., an iontophoretic device.
  • the pharmaceutical compositions described herein can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Rathbone et al., eds., 2008, Remington: The Science and Practice of Pharmacy, supra ; Modified-Release Drug Delivery Technology, 2nd ed., New York, NY: Marcel Dekker, Inc. ).
  • the pharmaceutical compositions described herein can be administered by a health care practitioner or , where appropriate, by the subject. In some embodiments, the subject administers the a post-perturbation treatment as described in Section 5.2 or a growth-promoting agent as described in Section 5.3 to him or herself.
  • topical administration is to the skin, either to the skin surface, transdermally, or intradermally. Topical administration can be with or without occlusion with a bandage or other type of dressing. In some embodiments, topical administration is to orifices or mucosa, or conjunctival, intracorneal, intraocular, ophthalmic, auricular, nasal, vaginal, urethral, respiratory, and rectal administration.
  • the formulation used for topical administration can be designed to retain the hair growth-promoting agent (or other active ingredient) in the skin or to deliver a dose of the hair growth-promoting agent systematically.
  • topical administration of a hair growth-promoting agent is combined with another treatment described herein, such as, but not limited to, a technique of integumental perturbation described in Section 5.1 supra.
  • Dosage forms that are suitable for topical administration for preferably local but also possible systemic effect include emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, powders, crystals, foams, films, aerosols, irrigations, sprays, suppositories, sticks, bars, ointments, bandages, wound dressings, microdermabrasion or dermabrasion particles, drops, and transdermal or dermal patches.
  • the topical formulations can also comprise micro-and nano-sized capsules, liposomes, micelles, microspheres, microparticles, nanosystems, e.g., nanoparticles, nano-coacervates and mixtures thereof. See, e.g., International Patent Application Publication Nos. WO 2005/107710, published November 17, 2005 , and WO 2005/020940, published March 10, 2005 , each of which is incorporated herein by reference in its entirety.
  • the nano-sized delivery matrix is fabricated through a well-defined process, such as a process to produce the hair growth-promoting agent encapsulated in a polymer.
  • the hair growth-promoting agent is spontaneously assembled in aqueous solutions, such as in liposomes and micelles.
  • the formulation for topical administration is a shampoo or other hair product, tanning product or sun protectant, skin lotion, or cosmetic.
  • the selected formulation will penetrate into the skin and reach the hair follicle.
  • the stratum corneum and/or epidermis are removed by a method of integumental perturbation described herein (including by wounding or scar revision, by laser, or by dermabrasion or microdermabrasion, which is a less vigorous form of dermabrasion), permitting application of the dosage form for topical administration directly into the exposed dermis.
  • the formulation for topical administration will be lipid-based, so that it will penetrate the stratum corneum.
  • the formulation for topical administration will contain a skin penetrant substance, such as, e.g., propylene glycol or transcutol.
  • a formulation in ointment form comprises one or more of the following ingredients: wool alcohol (acetylated lanolin alcohol), hard paraffin, white soft paraffin, liquid paraffin, and water. See, e.g., Langtry et al., supra.
  • the selected formulation is inconspicuous when applied to the skin, for example, is colorless, odorless, quickly-absorbing, etc.
  • the selected formulation is applied on the skin surface as a solution, which can crosslink into a hydrogel within a few minutes, thus creating a biocompatible dressing.
  • the hydrogel may be biodegradable.
  • the solution will absorb into the skin and crosslink into depots releasing drug.
  • the hair growth-promoting agent will be used to crosslink the polymer, with release of the hair growth-promoting agent controlled by the rate of degradation of the hydrogel.
  • the drug is encapsulated in microspheres, e.g., of sizes between 0.10 microns and 200 microns, or between 0.20 microns and 50 microns.
  • the drug is encapsulated in liposomes, e.g., of sizes between 10 nm and 50 microns, or between 500 nm and 20 microns.
  • the drug is applied in the form of liposomes or self-ordered vesicles such as multi-micellar aggregates of size ranges 0.1-100 nm, 100-1000 nm, 1-10 microns, 10-100 microns.
  • the drug (or, e.g ., the post-perturbation treatment) is administered as a cold liquid, which gels at a temperature of 32 °C - 37 °C.
  • the drug may be administered as a liquid, which then hardens into a depot that delivers drug over time.
  • the drug, or post-permeation treatment is administered as a hydrogel.
  • the post-perturbation treatment or drug-containing composition comprises propylene glycol, polyethylene glycol or ethanol.
  • the drug-containing composition comprises one or more excipients that complex to the drug.
  • the excipient comprises hyaluronic acid, polyacrylic acid or alginic acid.
  • the composition comprises one or more permeation enhancing agents or carriers that solubilize the drug in skin.
  • Pharmaceutically acceptable carriers and excipients suitable for use in topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
  • Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, mineral oil and other oils, white petrolatum, paraffins; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, wool alcohol (acetylated lanolin alcohol), and stearic acid ( see, Remington: The Science and Practice of Pharmacy,
  • Suitable cream base can be oil-in-water or water-in-oil.
  • Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase.
  • the oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier.
  • Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL ® ; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • compositions disclosed herein see, e.g., Sections 5.2, 5.3, and 5.4 supra .
  • Each of these methods of topical administration may be used alone to administer hair growth-promoting agents or in combination with one or more other treatments described herein.
  • topical administration is by electrical current, ultrasound, laser light, or mechanical disruption or integumental perturbation.
  • electroporation include electroporation, RF ablation, laserporation, laser ablation (fractional or non-fractional), non-ablative use of a laser, iontophoresis, phonophoresis, sonophoresis, ultrasound poration, or using a device that accomplishes skin abrasion, or microneedle or needle-free injection, such as topical spray or POWDERJECTTM (Chiron Corp., Emeryville, CA), BIOJECTTM (Bioject Medical Technologies Inc., Tualatin, OR), or JetPeelTM (from TavTech, Tel Aviv, Israel), which uses supersonically accelerated saline to remove epidermis.
  • POWDERJECTTM Chiron Corp., Emeryville, CA
  • BIOJECTTM Bioject Medical Technologies Inc., Tualatin, OR
  • JetPeelTM from TavTech, Tel Aviv, Israel
  • the device for topical administration is an automatic injection device worn continuously but delivers the hair growth-promoting agent or other active ingredients in a pulse fashion or intermittently.
  • the device for topical administration is an automatic injection device that is inconspicuous, for example, can be worn without undue discomfort under clothes, in the hair, under a hairpiece, etc.
  • a transdermal particle injection system such as, e.g., a "gene gun.”
  • a transdermal particle injection system such as, e.g., a "gene gun.”
  • Such systems typically accelerate drug or drug particles to supersonic velocities and "shoot" a narrow stream of drug through the stratum corneum.
  • the stratum corneum and epidermis is previously removed using a method of integumental perturbation described herein, and thus the required delivery pressures and velocities can be reduced. This reduction reduces the required complexity of the firing mechanisms.
  • a narrow firing stream is used, particularly to accomplish systemic delivery.
  • the particle injection system administers the pharmaceutical composition over a broad area of skin.
  • An exemplary particle delivery device compatible with broad-based skin delivery includes a low pressure / low velocity firing mechanism with a spray nozzle designed to deliver to a broad area.
  • a single-shot device that delivers to a 25-cm 2 area could be fired or used multiple times on the scalp or other skin surface until the entire area is treated.
  • a dry particle spraying mechanism similar to an airbrush or miniature grit-blaster can be used to "paint" drug or drug particles onto the perturbed area.
  • the stratum corneum and epidermis are already removed, e.g ., by a method of integumental perturbation described herein, and thus permits effective use of the mechanism using lowered pressure and velocity requirements to achieve dermal delivery.
  • the hair growth-promoting agent (and/or additional drug) is present in an aqueous suspension, permitting use of standard aerosol spray can technology to deliver the hair growth-promoting agent to the desired skin area.
  • the pharmaceutical composition can be administered using a two-chamber sprayer device, wherein the hair growth-promoting agent or other active ingredient is dispersed, solubilized, or emulsified in a liquid contained in one of the chambers.
  • the other chamber of the device would contain a liquid that is capable of reacting with the drug-containing liquid in the first chamber, to form a physically crosslinked hydrogel or a covalently linked hydrogel.
  • the liquids can react and form a drug-containing bioadhesive hydrogel to deliver the pharmaceutical composition to the desired area.
  • the drug-containing hydrogel will have additional features of supporting cell attachment and proliferation.
  • the pharmaceutical composition will be sprayed as a dry powder that is adherent to the underlying tissue.
  • dermabrasion e.g. , using a mechanical device, including microdermabrasion devices that can be used to dermabrade, or alumina-, silica- or ice-based dermabrasion (as described by Weber, U.S. 6,764,493 ; U.S. 6,726,693 ; and U.S. 6,306,119 )
  • a mechanical device including microdermabrasion devices that can be used to dermabrade, or alumina-, silica- or ice-based dermabrasion (as described by Weber, U.S. 6,764,493 ; U.S. 6,726,693 ; and U.S. 6,306,119 )
  • the device could also fire smaller drug particles that would simultaneously embed in the exposed dermis.
  • the device could switch over to firing drug particles once it is determined that adequate skin disruption has occurred. See, International Patent Application Publication No. WO 2009/061349 , which is incorporated herein by reference in its entirety.
  • a standard dermabrasion device can be modified to incorporate any of the devices described herein, e.g., a spraying/painting device.
  • a spray nozzle is located behind the dermabrasion wheel such that drug is sprayed into the dermis as it is exposed by the wheel.
  • the dermabrasion device via internal controls, could turn off the abrasion wheel once it is determined that adequate skin disruption has occurred, and switch on the drug spray to convert to drug painting mode.
  • the dermabrasion tip, dermabrader, and/or kit for dermabrasion described in Section 5.1 supra may be modified in accordance with these embodiments.
  • a non-fractional CO 2 or erbium-YAG laser is combined with drug spraying either without skin disruption, in conjunction with skin disruption, or following skin disruption.
  • a pulsed dye laser (585-595 nm) is combined with drug spraying either before or without skin perturbation, in conjunction with skin perturbation, or following skin perturbation.
  • a fractional non-ablative laser e.g., an Erbium-YAG laser used at 1540-1550 nm
  • a fractional ablative laser e.g., an erbium-YAG laser used at 2940 nm or a CO 2 laser used at 10,600 nm
  • drug spraying either without skin perturbation, in conjunction with skin perturbation, or following skin perturbation.
  • fractional ablative laser treatment of the skin e.g., an erbium-YAG laser used at 2940 nm or a CO 2 laser used at 10,600 nm
  • drug delivery e.g., an erbium-YAG laser used at 2940 nm or a CO 2 laser used at 10,600 nm
  • a fractional laser could be combined with a precise delivery means such that as the laser forms a hole in the skin, the inkjet-like delivery component could fill that same hole with drug.
  • adequate integrated hardware and software controls are required such that the laser ablation and drug delivery are properly timed resulting in each newly formed hole being properly filled with drug.
  • fractional ablative laser treatment of the skin e.g., an Erbium-YAG laser used at 2940 nm or a CO 2 laser used at 10,600 nm
  • drug delivery e.g., an Erbium-YAG laser used at 2940 nm or a CO 2 laser used at 10,600 nm
  • a non-ablative, fractional laser could be combined with a precise delivery means such that as the laser forms a hole in the skin, the inkjet-like delivery component could fill that same hole with drug.
  • adequate integrated hardware and software controls are required such that the laser treatment and drug delivery are properly timed resulting in each newly formed hole being properly filled with drug.
  • topical administration comprises administration of drug-containing particles.
  • the particles can be delivered to the skin in combination with any of the means described herein.
  • particles with different release properties are delivered simultaneously to achieve controlled delivery of drug.
  • topical administration comprises administration of a hair growth-promoting agent-containing formulation that is delivered through channels that are created by the use of micro-needle technology.
  • the formulation can be, e.g., a liquid, a gel or a dry spray.
  • topical administration may be through delivery of a hair growth-promoting agent-containing formulation through hollow needles.
  • topical administration comprises administration of a drug-containing formulation that is delivered into the skin by an iontophoretic patch.
  • a patch can be developed in which the drug-containing formulation is incorporated.
  • topical administration comprises administration of a drug-containing formulation that is incorporated into micro-needle shaped biodegradable polymers.
  • the biodegradable microneedles penetrate the targeted skin tissue, and are optionally left in place to deliver the drug in a sustained fashion over time.
  • the device or drug sprayer 2 includes a control unit or generator 4, a foot switch 6, a hand piece 8, and a power module 10.
  • the control unit 4 is the interface between the foot switch 6, the hand piece 8, and the power module 10. It serves as the central point of connectivity and provides a user with a means to power the system on or off, load/eject a drug cartridge into/from the hand piece 8, and select the drug delivery speed. To control all of this functionality, the control unit 4 includes at least one circuit board that controls operation of the hand piece 8 via embedded software.
  • the control unit 4 comprises a housing 12 that includes a hand piece connection port 14, a load/eject button 16, a means 18 to control the drug delivery or spray speed, a means 20 to display the drug delivery speed, an on/off switch 22, and a handle 24.
  • the means 18 to control the drug delivery speed includes a pair of up/down buttons and the means 20 to display the drug delivery speed comprises 8 discreet LEDs (light-emitting diodes) that light up to indicate the drug delivery speed.
  • Examples of materials that can be used for the load/eject button 16, the up/down buttons 18, and the on/off switch 22 include, but are not limited to, elastomeric materials such as silicon rubber, plastics, and metals.
  • the housing 12 can be made from an injection molded thermoplastic material such as, for example, acrylonitrile butadiene styrene.
  • FIGS 19A and 19B depict an embodiment of the drug sprayer's hand piece 8.
  • the hand piece 8 comprises a housing 26, a drive motor 28, a universal joint 30 and at least one plunger 32. Attached to the end of the hand piece 8 is a drug cartridge 34 that can either be disposable or reusable.
  • the hand piece's housing 26 can be made from an injection molded thermoplastic material such as, for example, acrylonitrile butadiene styrene. It will be readily apparent to those skilled in the art that other materials may be used to construct the hand piece's housing 26.
  • Some therapeutic compounds may quickly become unstable after their components are mixed or some may have a short shelf life unless they are refrigerated. Thus, in order to keep these compounds stable and increase shelf life, the components of the compounds are isolated from each other until the compounds are ready to be administered when they are mixed together forming, for example, a gel, controlled release, drug delivery matrix.
  • Prior devices such as those described in U.S. Patent No. 4,381,778 , U.S. Patent No. 4,689,042 , U.S. Patent No. 5,122,117 , and U.S. Patent No. 5,423,752 , the entirety of each are expressly incorporated herein by reference thereto, have been developed to store drug components separately and then mix the components prior to being dispensed.
  • Figures 20A-21E depict embodiments of a drug cartridge having two separate chambers that keep the drug components isolated until the therapeutic compound is to be dispensed.
  • Figures 20A-20D depict a drug cartridge 40 that contains two liquid components and its associated hand piece 42.
  • the drug cartridge 40 includes a housing 44 having a front end 46, a back end 48, a nozzle 50, a static mixer 52 having a mixing chamber 54 and two piercing elements 56 that extend from the back end 48 thereof and which are in fluid communication with the mixing chamber 54, two liquid component chambers 58, 60, a first liquid component 62 stored in the first component chamber 58, a second liquid component 64 stored in the second component chamber 60, and a piston 66 inserted into the back end 48 of each component chamber 58, 60 to rearwardly confine each liquid component 62, 64 within its respective component chamber 58, 60.
  • the pistons 66 form an airtight seal with the interior walls of their respective component chambers 58, 60.
  • a pierceable seal 68 is included to seal off the front end of each chamber 58, 60.
  • the piercing elements 56 penetrate the pierceable seals 68 of the first and second component chambers 58, 60, thereby forming a fluid connection between the static mixer 52 and the first and second component chambers 58, 60.
  • the mixing chamber 54 includes mixing elements 70 therein.
  • these mixing elements 70 can be pathways or channels formed in the interior walls of the mixing chamber 54 or can be mixing vanes that cause the liquid components 62, 64 to swirl as they travel through the mixing chamber 54 resulting in turbulent fluid flow, thereby mixing the liquid components 62, 64 together.
  • a user inserts the drug cartridge 40 into the front end 72 of the hand piece 42.
  • detents 74 on the drug cartridge 40 engage detents 76 on the hand piece 42 and lock the drug cartridge 40 and the hand piece 42 together.
  • the connecting portions 78 of each plunger 80 engage a corresponding cavity 82 in the pistons 66, forming a press-fit connection between the two.
  • the pistons 66 move in a corresponding manner.
  • the user When a user desires to dispense the therapeutic compound, the user activates the hand piece 42 via the control unit 4. Activation of the hand piece 42 in turn energizes the drive motor 28, which acts through a universal joint (see Figures 19A and 19B ) to move or drive the plungers 80 towards the front end 46 of the drug cartridge 40.
  • the pistons 66 move into the component chambers 58, 60 in a corresponding manner, forcing each separate liquid component 62, 64 through the piercing elements 56 and into the mixing chamber 54.
  • the turbulent flow created therein causes the liquid components 62, 64 to mix with each other.
  • the newly mixed components then exit the nozzle 50 as the mixed therapeutic compound 81.
  • the drug sprayer 2 can be used with a drug cartridge 84 that contains a liquid component 86 and a solid component 88.
  • the drug cartridge 84 includes a housing 90 having a front end 92, a back end 94, a lower chamber 96, a nozzle 98, a liquid component chamber 100 that houses the liquid component 86, a solid component chamber 102 that houses the solid component 88, a first piston 104 inserted into the back end of the liquid component chamber 100 to rearwardly confine the liquid component 86 therein, and a second piston 106 inserted into the back end of the solid component chamber 102 to rearwardly confine the solid component 88 therein.
  • the first and second pistons 104, 106 form an airtight seal with the interior walls of the liquid and solid component chambers 100, 102.
  • the front end 92 of the liquid component chamber 100 includes a first one-way or check valve 108 that confines the liquid component 86.
  • the front end 92 of the solid component chamber 102 does not include a check valve. Instead, a second check valve 110 is included at the back end of the of the lower chamber 96.
  • An example of such a one-way valve that can be used with the present drug cartridge 84 is a duck bill valve.
  • This configuration of the first and second check valves 108, 110 allows the liquid component 86 and the solid component 88 to be stored separate from each other and also closes the front ends of the liquid and solid component chambers 100, 102 forming a sealed volume of air between the first and second pistons 104, 106 and the first and second check valves 108, 110.
  • a user inserts the drug cartridge 84 into the front end 112 of the hand piece 114.
  • detents 116 on the drug cartridge 84 engage detents 118 on the hand piece 114 and thereby lock the drug cartridge 84 and the hand piece 114 together.
  • the hand piece 114 for use with the liquid-solid drug cartridge 84 includes a single plunger 120, which is inserted into the solid component chamber 102.
  • the user When a user desires to dispense the therapeutic compound, the user activates the hand piece 114 via the control unit 4. Activation of the hand piece 114 in turn energizes the drive motor 28, which acts through a universal joint 30 (see Figures 19A and 19B ) to move the plunger 120. Initially, the plunger 120 is retracted in the direction shown by arrow 126 in Figure 21D causing the second piston 106 to move in a corresponding manner. Because of the air tight seals created by the first and second pistons 104, 106 and the first and second check valves 108, 110, as can be seen in Figure 21D , as the second piston 106 retracts, negative pressure or suction is created in the solid component chamber 102.
  • This negative pressure or suction causes the first piston 104 to move in the direction of arrow 128 forcing the liquid component 86 through the first check valve 108 and into the liquid component chamber 102.
  • turbulent fluid flow is created, which operates to mix the liquid and solid components 86, 88 together.
  • the negative pressure within the closed system acts to keep the second check valve 110 closed.
  • a user can dispense the mixed drug by reversing the direction of travel of the plunger 120 as shown by arrow 130 in Figure 21E .
  • the amount of the liquid component 86 that is added to the solid component 88 and, hence, the concentration of the mixed drug can be controlled by adjusting the distance that the plunger 120 is retracted before reversing the direction of travel of the plunger 120 and dispensing the mixed drug. Therefore, for example, the further back that the plunger 120 is retracted, the more liquid component 86 enters into the solid component chamber 102 and thus, the more dilute the therapeutic compound becomes.
  • the first liquid component 62 is a solution comprising a hair growth-promoting agent salt and the second liquid component 64 is a polymeric solution that comprises a water-soluble polymer that is a solution at room temperature (20-25°C) and below, but gels at physiological temperatures of 32-37°C.
  • the hair growth-promoting agent concentration in the hair growth-promoting agent solution can be at least 1.2 times, 1.4 times, 1.6 times, 1.8 times, 2 times, 2.2 times, 2.4 times, 2.6 times, 2.8 times, 3 times, 4 times, or at least 5 times the concentration of the final concentration.
  • the hair growth-promoting agent solution can be a water-based solution.
  • the liquid component 86 is a polymeric solution that comprises a water-soluble polymer that is a solution at room temperature (20-25°C) and below, but gels at physiological temperatures of 32-37°C and the solid component 88 comprises a hair growth-promoting agent as described herein (see, e.g., Section 5.1).
  • either the drug spraying device, the drug cartridge, or both may be manufactured as a disposable.
  • the drug spraying device may be altered so that it is battery powered.
  • the components of the present device can be modified to dispense a therapeutic compound that comprises more than two components that need to be mixed together prior to dispensing.
  • a device for spraying a therapeutic compound comprises:
  • a device for spraying a therapeutic compound comprises:
  • a drug cartridge for use in a device for spraying a therapeutic compound comprises:
  • the drug spraying device disclosed herein enables the sustained release of drug, e.g ., hair growth-promoting agent or other active ingredient, without the use of highly hydrophobic, occlusive matrices.
  • the drug spraying device enables the delivery of drug in microspheres (e.g., PLG microspheres) such that the microspheres stay at the wound site for a prolonged period of time and are not cleared rapidly by phagocytosis.
  • a prolonged period of time can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or at least 20 days.
  • the drug spraying device enables the administration of drug-containing microspheres to the tissue such that the microspheres are sequestered to the wound surface by an in-situ crosslinking hydrogel that will form molecular bonds with the tissue surface.
  • An in-situ crosslinking hydrogel cannot be "rubbed” off like an ointment or a cream.
  • the microspheres will be sequestered in the hydrogel, releasing drug in a sustained manner.
  • the issue of phagocytosis of the microspheres is overcome.
  • the solid component 88 comprises a polymer macromonomer (Polymer 1) (a polymer that can further crosslink with another component) and microspheres containing a hair growth-promoting agent.
  • the liquid component 86 comprises another polymer macromonomer (Polymer 2) that is capable of reacting with Polymer 1.
  • Polymer 2 does not contain hydrolytically labile linkages and is stable in water.
  • the drug spraying device disclosed herein enables the sustained release of drug, e.g., hair growth-promoting agent or other active ingredient, and uptake by the skin through a scab.
  • the drug spraying device enables the delivery of hair growth-promoting agent such that the delivery system is incorporated into the scab. This can be accomplished by placing a hair growth-promoting agent containing thin, gauze-like, pliable biodegradable scaffold on the fresh wound. The material properties of the scaffold will be adjusted such the gauze is able to absorb the blood and other exudates from the wound.
  • the biodegradable scaffold has high content of void space, to absorb blood, fibrin and fibrinogen.
  • this incorporation of the scaffold into the fibrin clot during its formation results in its incorporation into the fibrous network, also called a scab, after it solidifies.
  • an in-situ crosslinking hydrogel may be applied on top to cover the entire site as a wound dressing.
  • the solid component 88 comprises a polymer macromonomer (Polymer 1) (a polymer that can further crosslink with another component) and the liquid component 86 comprises another polymer macromonomer (Polymer 2) that is capable of reacting with Polymer 1.
  • Polymer 2 does not contain hydrolytically labile linkages and is stable in water. Mixing of these two components yields a cross-linking hydrogel that is applied to the wound.
  • the cross-linking hydrogel is applied together with a biodegradable scaffold that comprises hair growth-promoting agent.
  • the biodegradable scaffold can be in the form a pliable, gauze-like material that is a blend of PLG polymers.
  • the cross-linking hydrogel is applied to the wound before the scaffold is applied; the cross-linking hydrogel is applied to the wound at the same time when the scaffold is applied; the cross-linking hydrogel is applied to the wound after the scaffold is applied.
  • the biodegradable scaffold has an "open-cell” structure that would allow cells to attach themselves, differentiate and proliferate.
  • the scaffold can have other components such as RGD peptides, etc. incorporated to encourage cell attachment.
  • the scaffold can have bioadhesive attributes to keep it "in place.”
  • the drug spraying device disclosed herein enables the concurrent delivery of two or more drugs with different solubility properties and/or physical/chemical incompatibilities (such as different excipient requirements; binding and / or reaction of the two or more drugs with each other).
  • the first liquid component 62 is a first formulated drug and the second liquid component 64 is a second formulated drug.
  • the presently disclosed drug spray device can be engaged for spraying each drug separately.
  • an alcoholic solution ⁇ drug
  • both chambers could contain the same drug, but in different forms and formulated differently to achieve different release profiles.
  • the first liquid component 62 could contain micronized hair growth-promoting agent suspended in a FDA-approved liquid excipient and the second liquid component 64 can be a dissolved hair growth-promoting agent in an aqueous sprayable gel. Co-spraying both forms of hair growth-promoting agent provides instantly-bioavailable, hair growth-promoting agent and a sustained form of hair growth-promoting agent made available as the micronized hair growth-promoting agent dissolves.
  • the drug spraying device disclosed herein enables the cleansing and administration of one or more drugs with one single device.
  • the contents of each chamber could be sprayed separately.
  • Once chamber can contain the cleansing solution; the liquid in the other chamber contains a hair growth-promoting agent. Any wound-cleansing solution known to the skilled artisan can be used with these embodiments.
  • a device for spraying a therapeutic compound comprising:
  • a device for spraying a therapeutic compound comprises:
  • a drug cartridge for use in a device for spraying a therapeutic compound comprises:
  • the drug spraying device disclosed herein enables the sustained release of a hair growth-promoting agent, without the use of highly hydrophobic, occlusive matrices.
  • the drug spraying device enables the delivery of a hair growth-promoting agent in microspheres (e.g., PLG microspheres) such that the microspheres stay at the wound site for a prolonged period of time and are not cleared rapidly by phagocytosis.
  • a prolonged period of time can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or at least 20 days.
  • the drug spraying device disclosed herein enables the sustained release of a hair growth-promoting agent and uptake by the skin through a scab.
  • the drug spraying device enables the delivery of a hair growth-promoting agent such that the delivery system is incorporated into the scab.
  • This can be accomplished by placing a hair growth-promoting agent-containing, thin, gauze-like, pliable biodegradable scaffold on the fresh wound. The material properties of the scaffold will be adjusted such the gauze is able to absorb the blood and other exudates from the wound.
  • the biodegradable scaffold has high content of void space, to absorb blood, fibrin and fibrinogen.
  • an in-situ crosslinking hydrogel is applied on top to cover the entire site as a wound dressing.
  • the drug spraying device disclosed herein enables the concurrent delivery of two or more drugs with different solubility properties and/or physical/chemical incompatibilities (such as different excipient requirements; binding and / or reaction of the two or more drugs with each other).
  • the drug spraying device disclosed herein enables the cleansing and administration of one or more drugs with one single device.
  • the contents of each chamber could be sprayed separately.
  • Once chamber can contain the cleansing solution; the liquid in the other chamber contains a hair growth-promoting agent. Any wound-cleansing solution known to the skilled artisan can be used with these embodiments.
  • compositions described herein can be parenteral by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • Compositions for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents,
  • compositions for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the compositions are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
  • compositions described herein, e.g., for use in post-perturbation treatments described in Section 5.2, or comprising hair growth-promoting agents (Section 5.3) and/or other active ingredients (Section 5.4) disclosed herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • Compositions for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458 .
  • compositions described herein may also be administered to skin-derived cells or skin tissue ex vivo.
  • a hair growth-promoting agent treatment may be used to enhance the re-association of dissociated hair follicle cells into follicles and their growth and expansion in culture for their implantation into fresh wounds and scar revisions.
  • hair follicles promoted by a hair growth-promoting agent treatment are added to an area of skin before, at the time of, and/or subsequent to, integumental perturbation.
  • hair follicles can be introduced to the wound by migration, reorganization, stimulation, or activation, or de novo hair follicle neogenesis, or by transplanting one or more of the following skin elements: full skin (xeno-; autologous human), follicular units, dissociated cells (donor dominance; recipient effects), ex vivo-expanded skin and/or follicular units, or human skin equivalents in vivo (universal donors).
  • Engineered human skin, or human skin equivalents can also be used for hair follicle formation and activation and scar revision platforms.
  • Human skin equivalents can be grown and assembled in vitro, with the advantage that they can be grown to theoretically to any size/shape; can be comprised of different types of cells, including keratinocytes (hair follicle derived and non-hair follicle derived), dermal cells (hair follicle derived and non-hair follicle derived), other cell types (e.g., mesenchymal stem cells); can contain cells that are genetically modified to include, e.g ., markers or "inducible" signaling molecules; provide an unlimited and uniform source of human cells; from normal skin based on histology and marker studies; are generally devoid of skin appendages; and can be wounded and show similar wound healing events as in vivo.
  • keratinocytes hair follicle derived and non-hair follicle derived
  • dermal cells hair follicle derived and non-hair follicle derived
  • other cell types e.g., mesenchymal stem cells
  • modified release dosage forms can be formulated as modified release dosage forms.
  • modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphism of the active ingredient(s).
  • the controlled release is achieved by using an adjuvant that causes a depot effect, i.e., that causes an active agent or antigen to be released slowly, leading to prolonged exposure to a target cell or tissue (e.g., cells of the follicle, or, in the case of immunostimulatory adjuvants, prolonged exposure to the immune system).
  • a target cell or tissue e.g., cells of the follicle, or, in the case of immunostimulatory adjuvants, prolonged exposure to the immune system.
  • modified release examples include those described in International Patent Application Publication No. WO 2008/115961, published September 25, 2008 , which is incorporated herein by reference in its entirety.
  • modified release examples include, but are not limited to, those described in U.S. Pat.
  • the modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art. See, Takada et al., 1999, in Encyclopedia of Controlled Drug Delivery, Mathiowitz E, ed., Vol. 2, Wiley .
  • the modified release dosage form is formulated using an erodible matrix device, which is water-swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • an erodible matrix device which is water-swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate
  • the compositions are formulated with a non-erodible matrix device.
  • the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers,
  • the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
  • modified release dosage forms can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
  • the modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • an osmotic controlled release device including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • AMT asymmetric membrane technology
  • ECS extruding core system
  • such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core.
  • the semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmotic agents water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.”
  • Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl
  • osmogens which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, gluta
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as MANNOGEMTM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
  • the core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copo
  • a semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119 .
  • Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220 .
  • the total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • An osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See Remington: The Science and Practice of Pharmacy, supra ; Santus and Baker, J. Controlled Release 1995, 35, 1-21 ; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708 ; and Verma et al., J. Controlled Release 2002, 79, 7-27 .
  • compositions are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers.
  • AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • compositions are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
  • a pharmaceutical composition described in Section 5.2, Section 5.3, and/or Section 5.4 supra can be formulated as a polymeric solution that consists of a water-soluble polymer that is a solution at room temperature (20-25°C) and below, but gels at physiological temperatures of 32-37°C.
  • the solution can be cooled to 2-8°C to impart a soothing effect, while being sprayed as a liquid spray on the tissue surface. Once sprayed on, the solution will thicken into a gel, releasing the any drug contained therein slowly over time.
  • the solution can be injected as a liquid, to form an in situ depot within the tissue.
  • the solution can be delivered as a solution, which can flow into orifices of the tissue, such as hair follicles and then form a gel to release the hair growth-promoting agent for follicle-associated conditions, such as MPHL, folliculitis, or another condition described herein.
  • the temperature and time of gelation can be correlated to the concentration of the polymers and the length of the polymer blocks that constitute the polymers.
  • the a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 ⁇ m to about 3 mm, about 50 ⁇ m to about 2.5 mm, or from about 100 ⁇ m to about 1 mm in diameter.
  • multiparticulates can be made by the processes known to those skilled in the art, including microfluidization, membrane-controlled emulsification, oil-in-water, water-oil-water and oil-in oil emulsification and homogenization processes, complex coacervation, wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores.
  • excipients or carriers as described herein can be blended with the compositions to aid in processing and forming the multiparticulates.
  • the resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers.
  • the multiparticulates can be further processed as a capsule or a tablet.
  • compositions for use herein may be formulated with a carrier that delivers the hair growth-promoting agent or other active ingredient(s) to the site of action, for example, a follicle in a particular tissue.
  • a carrier that delivers the hair growth-promoting agent or other active ingredient(s) to the site of action, for example, a follicle in a particular tissue.
  • Such targeted delivery may be preferable in formulations for systemic administration, in order to reduce side effects associated with therapy with the hair growth-promoting agent or other active ingredient(s) and/or ensure that the hair growth-promoting agent or other active ingredient(s) reaches only follicles of particular tissues.
  • the carrier may be an aptamer targeted to a particular protein or cell type in the follicle, an antibody or antigen-binding fragment thereof, a virus, virus-like particle, virosome, liposome, micelle, microsphere, nanoparticle, or any other suitable compound.
  • compositions for use in the methods provided herein can also be formulated to be targeted to a particular tissue, follicle, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos.
  • targeting is accomplished by the attachment of specific targeting moieties to the delivery systems containing the drug.
  • Targeting moieties can be in the form of antibodies, aptamers or small molecules that bind to specific proteins expressed in specific tissues.
  • Specific or guided targeting can "channel" the drug only to the specific tissue type, thus minimizing distribution to all tissues. This concept is especially useful if the drug causes side effects.
  • microspheres and nanospheres have been utilized, to deliver drugs into the hair follicle. Entry into the hair follicle is governed by the size of the drug-containing spheres, with microspheres of size 0.5-0.7 microns of ideal size for entry.
  • the surface of the microspheres can be functionalized with moieties that bind to specific surfaces in the follicular orifice to "retain" them at the site.
  • These moieties can be non-specific, such as hydrophobic coatings, or cationic coatings, in order to be bioadhesive to cells within the follicle.
  • the moieties can be specific and targeted to certain proteins that are expressed specifically on specific cell membranes. For example, proteins over-expressed on the follicular lymphoma cell surfaces can be targeted by delivery systems that have antibodies or aptamers designed to bind to these proteins.
  • the surface of the delivery systems can also be functionalized with cell-penetrating moieties such as cell-permeable peptides, positively charged polymers that bind to anionic cell surfaces.
  • the dosage of any systemically administered drug is tightly controlled. Another way in which such side effects may be circumvented is to deliver the drug locally to the site where hair growth modulation is desired.
  • the hair growth-promoting agents or other active ingredient(s) described herein may be delivered locally to any part of the subject in which modulation of hair growth is desired, including, e.g., the head ( e . g ., the scalp, cheek, chin, upper lip, lower lip, ears, nose, eyelashes, or eyebrow), neck, abdomen, chest, breast, e.g., the nipples, back, arms, armpits (axillary hair), stomach, genital area, buttocks, legs, hands, or feet of a subject.
  • hair growth-promoting agent is applied or administered to wounded or scarred skin.
  • Such local delivery of the hair growth-promoting agent or other active ingredient(s) can be achieved by topical administration, transdermal, intradermal, subcutaneous (depot effect), or by intramuscular, intravenous and oral routes of delivery in formulations for targeting systemically delivered hair growth-promoting agent to desired follicles.
  • Such modes of delivery are discussed supra.
  • enhancement of hair follicle formation in integumentally perturbed skin is accomplished by treatment with a pharmaceutical combination described herein in combination with a pre-designed biomaterial dressing that may serve as a substrate to encourage a step-wise attachment of keratinocytes and epithelial cells to it, such that formation of an organized extra-cellular matrix (ECM) is enhanced in order to promote wound healing.
  • ECM organized extra-cellular matrix
  • the scaffold for use in combination with treatment with a pharmaceutical composition described herein may be comprised of a mesh of a biocompatible, bioabsorbable material that cells recognize and attach to, preferably with ease.
  • these materials can be collagen type I/III, hyaluronic acid, chitosan, alginates, or combinations and derivatives thereof or any other such material described herein or known in the art.
  • the mesh scaffold may be neutral, or charged. If the mesh is positively charged, it may permit cells (which are negatively charged) to adhere to it more effectively. If the mesh scaffold is negatively charged, it may contain signaling moieties that the cells will recognize and attach to. For example, polymers such as hyaluronic acid are present already in skin, and thus a mesh comprised of this material is thought to be compatible with cells.
  • the scaffold is pre-fabricated with a fine microstructure that is of the dimension of cells, for example, red blood cells that will initially diffuse throughout the scaffold, or epithelial cells and keratinocytes from surrounding tissue.
  • a fine microstructure that is of the dimension of cells, for example, red blood cells that will initially diffuse throughout the scaffold, or epithelial cells and keratinocytes from surrounding tissue.
  • epithelial cells and keratinocytes from surrounding tissue.
  • the "epithelial tongue" can move with greater ease and organization by crawling on the scaffold mesh.
  • the mesh scaffold has an "open-cell” structure, with the pores inter-connected, much like an open-celled foam.
  • the open, interconnecting nature of the scaffold may allow free diffusion of oxygen and cells, so that optimal organized wound healing can occur.
  • the mesh scaffold has the capacity to hydrate and remain hydrated throughout the wound healing period. This is useful because, without being bound by any theory, drying out of the wound results in an impermeable granular structure that the keratinocytes cannot "crawl upon.”
  • the mesh scaffold has moieties that act as molecular signals to the cells, for example, to aid their proliferation.
  • moieties include, but are not limited to, peptidoglycans and RGD integrin recognition sequences that encourage cell attachment and subsequent proliferation.
  • the mesh scaffold has incorporated within it one or more active agents, for example, a small molecule, or a nucleic acid, or a protein.
  • the additional active agent is a protein, such as noggin or WNT, or is a nucleic acid that encodes noggin or WNT.
  • a small molecule is incorporated into the scaffold, such as, e.g., a hair growth-promoting agent (such as one or more hair growth-promoting agents described herein, or another hair growth-promoting agent), BMP inhibitor, or PPAR antagonist.
  • the compound incorporated in the mesh scaffold is a compound considered for use in the combination therapies described herein, for example, in Sections 5.2-5.4.
  • the scaffold may incorporate superoxide dismutase, a free radical quenching molecule that functions in the reduction of inflammation.
  • compounds are included in the mesh scaffold that alter the kinetics of wound healing, for example, that slow wound healing. Such compounds are known in the art and described elsewhere herein.
  • Other compounds that may be incorporated in the mesh scaffold include growth factors that aid in cell proliferation and tissue regeneration.
  • the compounds aid in hair follicle migration or the formation of new or activated follicular structures in the integumentally perturbed or wounded site.
  • a hair growth-promoting agent is incorporated within the mesh scaffold.
  • the hair growth-promoting agent is incorporated within one or more layers of a multilayered mesh scaffold.
  • the mesh scaffold contains the hair growth-promoting agent in alternating layers, which may achieve a pulsatile delivery of hair growth-promoting agent.
  • the hair growth-promoting agent is incorporated in microspheres in the scaffold, enabling a controlled release of hair growth-promoting agent from the scaffold.
  • the mesh scaffold can be fibrin gels that additionally contain hair growth-promoting agent.
  • a fibrin network is the first scaffold that a cell encounters as it performs its role in healing wounds due to trauma or other insults to tissue.
  • the fibrin network (the "scab") assemble rapidly by a modified polycondensation reaction from fibrinogen, an abundant constituent of blood plasma, as soon as the protease thrombin is activated in the clotting cascade-the result is a three-dimensional network of branching fibers, What is envisioned is a fibrin delivery matrix containing hair growth-promoting agent, fibrinogen and thrombin, that "gels" in situ.
  • One issue that is encountered is the ability of hair growth-promoting agent to diffuse through the fibrin "scab” - making the drug part of the scab solves this issue.
  • the mesh scaffold is a synthetic biodegradable dressing and hair growth-promoting agent delivery system that also acts as a "sponge" and absorbs the exudates/bloods from a wound or otherwise integumentally perturbed site.
  • These exudates intercalating with the synthetic scaffold contain an abundance of fibrinogen, thrombin, fibronectin, cell adhesion proteins, growth factors and hyaluronic acid, all of which create an integrated structure that is an attractive matrix for cell attachment /differentiation and delivery of hair growth-promoting agent.
  • the release rate of hair growth-promoting agent can be modulated by varying the composition of polymers that comprise the synthetic scaffold, or sponge.
  • a synthetic scaffold fabricated out of poly(lactide)-co-(glycolide) (PLG) and poly(lactide) (PLA) can be developed to have varied release profiles of hair growth-promoting agent. Changing the ratio of PLA to PLG will change the release profile of the hair growth-promoting agent from the scaffold.
  • Other polymers that can utilized to generate synthetic scaffolds are chitosan, carrageenan, alginate, poly(vinyl alcohol), poly(ethylene oxide) (PEO), poly(ethylene oxide)-co-poly(propylene oxide)-co-poly(ethylene oxide) (PEO-PPO-PEO), poly(acrylates) and poly(vinyl pyrrolidone) (PVP).
  • the rate of hair growth-promoting agent release from the formulation can be controlled, so that it takes anywhere from 2 hours to 30 days for most ( e . g ., 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 100%) of the hair growth-promoting agent to be released.
  • most of the hair growth-promoting agent is released from the formulation within 2 hours, within 4 hours, within 8 hours, within 16 hours, within 24 hours, within 36 hours, within 48 hours, within 3 days, within 5 days, within 7 days, within 10 days, within 14 days, within 30 days, or within 2 months or more.
  • the mesh scaffold releases the aforementioned compounds in a timed release manner, acting as a controlled release formulation such as described in Section 5.3.1 above.
  • the compounds may be bound to the mesh scaffold, and are then released at a sustained release manner as a result of de-binding kinetics from the mesh.
  • the compound may be bound to a polymer, which is then incorporated to the mesh scaffold, and which may allow the compound to diffuse from the mesh at a slow rate, resulting in sustained release.
  • the mesh scaffold is extruded as a gel, with certain components of the gel precipitating out to form a mesh in situ.
  • the in situ mesh can be sprayed on the wounded or otherwise perturbed surface, such as tissue that has been extensively burned. A large area can be covered in this manner.
  • the mesh scaffold is pre-fabricated as a dressing or a wrap, to cover large areas of wounded or otherwise perturbed tissue.
  • the mesh scaffold can be cut to size to fit the size of the wound or perturbed site to present a compatible surface for favorable movement of the epithelial tongue.
  • the scaffold is prepared by melt spinning, electrospinning, micromachining, weaving, or other methods known in the art in which open cell foams are fabricated.
  • the mesh scaffold can be fabricated by these methods, with the optional incorporation of additional compound(s) (which are optionally sterilized), then sterilized by gentle ethylene oxide sterilization.
  • the additional compounds are sterilized, and then added to the sterile mesh scaffold.
  • a combinatorial strategy that uses a biodegradable scaffold combined with integumental perturbation and, optionally, administration of a hair growth-promoting agent formulation or other pharmaceutical composition described herein is applied, which may result in the in situ generation of embryonic stem cells or recruitment of cells required for healing following wounding or other form of integumental perturbation.
  • This approach may be used together with a form of integumental perturbation described in Section 5.1 ( e . g ., dermabrasion accomplished by a standard dermabrader or a laser, deep full-thickness excision (as for deep burns) accomplished by a bulk ablative laser) or integumental perturbation by acute wounds, chronic wounds, or wounds generated for the purpose of scar revision.
  • integumental perturbation in combination with a scaffold that administers drug results in the in situ generation of stem cells or recruitment of other cells required for the wound healing process and may facilitate more effective wound healing with little or no scarring.
  • the scaffold is biodegradable. Placement of a 3-dimensional biodegradable scaffold in the wound assists the attachment, growth and differentiation of cells.
  • tissue repair has been by autologous cell/tissue transplantation-however, autografts are associated with donor site morbidity and limited availability.
  • An alternative is allografts, but these are susceptible to immune responses and also carry the risk of disease transfer.
  • tissue engineering has emerged as an interdisciplinary field that makes use of biomaterials, cells and factors either alone, or in combination to restore tissues. The tissue engineering strategy generally involves isolation of healthy cells from a patient, followed by their expansion in vitro.
  • a fibrin network is the natural network that forms rapidly due to a polycondensation reaction from fibrinogen, an abundant constituent of blood plasma, as soon as the protease thrombin is activated in the clotting cascade. The fibrin clot then forms a three-dimensional network for cells to attach, for re-epithelialization.
  • the biodegradability of the scaffold is modulated.
  • the biodegradability of the scaffold should be matched to the formation of the new epithelium due to wound healing or other form of integumental perturbation.
  • One skilled in the art would know how to measure whether a synthetic matrix is biodegradable.
  • biodegradability can be measured ex vivo in implants or using rats or another animal model, by histological and HPLC analysis.
  • biodegradability by hydrolysis can be assessed.
  • the scaffold structure of choice is incubated in phosphate buffered saline, pH 7.4 and 37 °C.
  • the incubation buffer includes enzymes. The scaffolds are weighed prior to incubation.
  • the scaffolds are retrieved two-at-a-time at predetermined time points and dried in a vacuum oven.
  • the scaffolds are weighed at each time point and a plot of weight versus time is generated to develop the rate of biodegradability.
  • the biodegradability of the scaffold matrix is modulated to coincide with the healing process, and can be modulated by changing the composition of polymers utilized to fabricate the mesh.
  • a percentage of polyethylene glycol (PEG) can be included in a composition with PLG to increase biodegradation (for example, see ASTM E1279 - 89, 2008, Standard Test Method for Biodegradation By a Shake-Flask Die-Away Method).
  • Biodegradable synthetic matrices can be created to mimic the extra-cellular micro-environment for the enhanced cellular attachment necessary for tissue regeneration.
  • cell-recognition motifs such as RGD peptides may be incorporated to encourage cells to attach themselves to the scaffold.
  • biomimetic nature of the scaffold is judged on the basis of the content of the mesh and resultant intercalating fibrin.
  • the properties of the synthetic scaffold are dependent upon the three-dimensional geometry, matching of the modulus of the matrix with the tissue type and the porosity. It has been shown that the differentiation process can be modulated if the modulus of the tissue type is matched with the modulus of the scaffold.
  • the modulus of the scaffold is matched with the modulus of the tissue type.
  • the compressive modulus of a scaffold or hydrogel can be measured by a standard Instron instrument ( e . g ., using the TA Instruments DMA Q800).
  • the micro-environment created by the cells is optimally highly biocompatible to the cells present at the site, namely keratinocytes and stem cells derived from the dermal papilla.
  • this can be accomplished through the use of hydrophilic components that can absorb water.
  • hydrophobic components such as petrolatum is likely to be occlusive and prevent rapid cell proliferation.
  • the scaffold is incubated with human foreskin fibroblasts (HFF) in vitro and the scaffold is considered to be biocompatible if the cells maintain their shape and attach appropriately.
  • HFF human foreskin fibroblasts
  • the biodegradable scaffold is permeable to water, nutrients, oxygen and growth factors, enabling easy exchange of nutrients between tissues and cells (see, e.g., ASTM D39857). In some embodiments, a non-occlusive, non-permeable barrier is avoided.
  • the scaffold is used to "fill" a deep wound, as is common in a deep burn, to provide a matrix for the cells to attach, grow and differentiate - existence of the scaffold will likely minimize the scar formation normally observed in deep, large-area wounds.
  • a loose, dry, highly porous network or scaffold or mesh is placed in the bleeding site of the wound or otherwise integumentally perturbed site to gently absorb the blood and the cell adhesion proteins released at the site.
  • This will result in creation of a highly rich environment that consists of a combination of a 3-dimensional scaffold combined with fibrinogen and thrombin, which will ultimately result in a highly biocompatible hydrogel suitable for cell attachment and growth.
  • inclusion of blood components and cell adhesion proteins into the network is critical for establishment of the ECM (extracellular matrix) necessary to form continuous tissue ingrowth, particularly in the case of large-area and deep wounds.
  • a dry scaffold has the added advantage of absorbing the blood at the wound or otherwise integumentally perturbed site.
  • a person's own blood components can be used to create a combined synthetic/natural ECM.
  • the scaffold has an added advantage of serving as a blood absorbing gauze.
  • the scaffold has cell-recognition motifs, such as RGD peptides, to recruit cells to the site and attachment, thereof. Once attached, cells will proliferate. Without being bound by any theory, it is hypothesized that the primary attachment of cells to the scaffold is a critical step to prevent premature cell death.
  • a dry, sterile biodegradable scaffold is placed onto the freshly formed wound or perturbed skin site.
  • the properties of the scaffold will be such that it will transform into an adherent hydrogel upon water absorption.
  • Nano-fiber meshes fabricated by electrospinning, hydrogel imprint technologies have been utilized to create three-dimensional microstructures that match the supramolecular architecture of the tissue type. In situ forming scaffolds are also contemplated.
  • the active agents are administered using an active agent-containing spray-on hydrogel.
  • the active agent after placement of the biodegradable scaffold, the active agent is sprayed on the tissue.
  • the active agent (or combination of active agents, e.g., a hair growth-promoting agent and a stem cell signaling agent) may be incorporated into a spray-on hydrogel that will be sprayed on as a liquid, but which transforms into a hydrogel after it is sprayed on the tissue. This will be especially useful if the area of the wound or integumental perturbation is large and uniform coverage is needed.
  • the active agent-containing spray-on hydrogel is applied on the wound or otherwise integumentally perturbed site, forming a cross-linked hydrogel that releases active agent over the time period of healing or a shorter or longer time period, as necessary.
  • the active agent will either be incorporated in micro-encapsulates or nano-encapsulates and suspended into the pre-hydrogel solution.
  • the active agent can also be dissolved into the pre-hydrogel solution.
  • the "pre-hydrogel" solution is defined as the solution that will be sprayed on the tissue and which also contains the active agent.
  • the active agent is contained within microspheres that can be positively charged to rapidly bind themselves to the negatively charged collagen present in the dermis. Binding the microspheres to the dermis renders the active agent-releasing moiety immobile at the site.
  • the wound or otherwise integumentally perturbed site may be covered with a breathable, non-occlusive spray-on hydrogel to cover the site from infection during healing.
  • a particular treatment can be administered prior to, concurrently with, or subsequent to the administration of a second (or third, or more) treatment.
  • the second or third or later treatment comprises treatment with the same active agent, albeit at a different ( e . g ., in one embodiment, higher) dose.
  • one treatment is administered to a subject at reasonably the same time as the other treatment.
  • This method provides that the two administrations are performed within a time frame of less than one minute to about five minutes, or up to about sixty minutes from each other, for example, at the same doctor's visit.
  • one treatment and another treatment are administered at exactly the same time.
  • one treatment and the other treatment are administered in a sequence and within a time interval such that the one treatment and the other treatment can act together to provide an increased benefit than if they were administered alone.
  • the one treatment and the other treatment are administered sufficiently close in time so as to provide the desired outcome.
  • Each can be administered simultaneously or separately, in any appropriate form and by any suitable route.
  • the one treatment and the other treatment are administered by different routes of administration.
  • each is administered by the same route of administration.
  • the one treatment and the other treatment can be administered at the same or different sites of the subject's body. When administered simultaneously, the one treatment and the other treatment may or may not be administered in a single formulation, a mixture of formulations, or at the same site of administration, or by the same route of administration.
  • the one treatment and the other treatment are administered less than I hour apart, at about 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • the one treatment and the other treatment are administered 2 to 4 days apart, 4 to 6 days apart, I week a part, 1 to 2 weeks apart, 2 to 4 weeks apart, one month apart, 1 to 2 months apart, 2 to 3 months apart, 3 to 4 months apart, 4 to 5 months apart, 6 months apart, 6 months to one year apart, or one year or more apart.
  • the one treatment and the other treatment are administered in a time frame where both are still active. One skilled in the art would be able to determine such a time frame by determining the half life of each administered component.
  • the one treatment and the other treatment are administered within the same patient visit. In one embodiment, the one treatment is administered prior to the administration of the other treatment. In an alternate embodiment, the one treatment is administered subsequent to the administration of the other treatment.
  • the one treatment and the other treatment are cyclically administered to a subject.
  • Cycling treatment involves the administration of one or more treatments once or for a period of time, followed by the administration of the other treatment once or for a period of time, and repeating this sequential administration.
  • the first treatment may be with the one treatment or with the other treatment, depending on the subject's prior treatment history and the intended outcome.
  • cycling treatment can also reduce the development of resistance to one or more of the treatments, avoid or reduce the side effects of one of the treatments, and/or improve the efficacy of the treatment.
  • alternating administration of the one or more treatments may be followed by the administration of another treatment (or vice versa) 1 year later, 6 months later, 3 months later, 1 month later, 3 weeks later, 2 weeks later, 1 week later, 4 to 6 days later, 2 to 4 days later, or 1 to 2 days later, wherein such a cycle may be repeated as many times as desired.
  • the one (or more) treatments and the other treatment are alternately administered in a cycle of 3 weeks or less, once every two weeks, once every 10 days or once every week.
  • Such time frames can be extended or reduced depending on properties of the treatment, e.g., whether a controlled release formulation is used, and/or depending on the progress of the treatment course.
  • subjects discontinue their current treatment (e . g ., topical minoxidil or finasteride), the area to be treated is integumentally perturbed, and the post-perturbation treatment is applied for 12 days. After 12 days, the post-perturbation treatment is discontinued, and treatment with the current treatment (or another hair growth-promoting agent, or a combination of hair growth-promoting agents) is re-started.
  • the subject is treated with 10 cycles of the protocol: integumental perturbation followed by post-perturbation treatment ( e .
  • hair growth-promoting agent e . g ., for 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.
  • the timing of treatment or a combination of treatments can be coordinated with the presence or absence of indicators of hair growth in a treated area of skin.
  • the timing of repeated treatments with integumental perturbation (optionally in combination with a post-perturbation treatment) or a treatment with integumental perturbation (optionally in combination with a post-perturbation treatment) preceded or followed by one or more hair growth-promoting agent treatments may be adjusted based on the appearance, or anticipated appearance, of one or more of the following indicators in a treated skin site: NL, PEL, and/or PELA follicular structures, pre-existing vellus hair, new vellus hair, vellus-to-terminal hair switch, terminal hair, terminal-to-vellus hair switch, etc.
  • integumental perturbation involving hair transplantation e . g ., follicular unit extraction
  • an area of scalp that was pre-treated with one or more hair growth-promoting agents e . g ., minoxidil or finasteride
  • a perturbation treatment is administered to the sites from which transplanted tissue will be obtained. This site undergoes post-perturbation treatment for one week, and then discontinued and followed by treatment with, e . g ., minoxidil or finasteride for three months.
  • integumental perturbation involving hair transplantation e . g ., follicular unit extraction
  • an area of scalp that was formerly a donor area in a previous hair transplant is treated before a subsequent hair transplant.
  • the former donor site is pre-treated with one or more hair growth-promoting agents, e . g ., minoxidil or finasteride, and this site will be used as a source for transplanted follicles.
  • a perturbation treatment is administered to the sites from which transplanted tissue will be obtained.
  • This site is integumentally perturbed, and the post-perturbation treatment is applied for one week, and then discontinued and followed by treatment with, e . g ., minoxidil or finasteride for three months or more.
  • integumental perturbation involving hair transplantation e . g ., follicular unit extraction
  • an area of scalp that was formerly a donor area in a previous hair transplant is treated before a subsequent hair transplant.
  • a perturbation treatment is administered to the sites from which transplanted tissue will be obtained without any pre-treatment with a hair growth-promoting drug, e.g. minoxidil or finasteride.
  • This site is integumentally perturbed, and the post-perturbation treatment is applied for one week, and then discontinued and followed by treatment with, e . g ., minoxidil or finasteride for three months or more.
  • integumental perturbation involving hair transplantation e . g ., follicular unit extraction
  • an area of scalp that has not been a donor area in a previous hair transplant but will be used in the future is treated before a subsequent hair transplant.
  • This site is pre-treated with one or more hair growth-promoting agents, e.g., minoxidil or finasteride, and this site will be used as a source for transplanted follicles.
  • a perturbation treatment is administered to the sites from which transplanted tissue will be obtained.
  • This site is integumentally perturbed, and the post-perturbation treatment is applied for one week, and then discontinued and followed by treatment with, e . g ., minoxidil or finasteride for three months or more.
  • integumental perturbation involving hair transplantation e.
  • follicular unit extraction accompanies treatment with one or more hair growth-promoting agents, an area of scalp that has not been a donor area in a previous hair transplant but will be used in the future is treated before a subsequent hair transplant.
  • a perturbation treatment is administered to the sites from which transplanted tissue will be obtained without pre-treatment with a hair growth-promoting drug, e.g. minoxidil or finasteride and the post-perturbation treatment is applied for one week, and then discontinued and followed by treatment with, e.g ., minoxidil or finasteride for three months or more.
  • integumental perturbation is performed in combination with one or more techniques of depilation (removal of the part of the hair above the surface of the skin) or epilation (removal of the entire hair, including the part below the skin) on a part of the skin to be treated.
  • Any form of epilation or depilation known in the art can be used.
  • Methods of depilation that can be used include, but are not limited to, shaving, the use of abrasive materials, a mechanical device, and the use of chemical depilatories (e . g ., Nair® or thioglycolic acid), which work by breaking the disulfide bonds that link the protein chains that give hair its strength, making the hair disintegrate.
  • Methods of epilation include, but are not limited to, plucking with tweezers, waxing, sugaring, epilation devices, threading, home pulsed light, laser, electrolysis, and can include the use of hair growth retardants (e . g ., Vanlqa® (eflornithine)). Prior to disruption, the skin can depilated or epilated.
  • hair growth retardants e . g ., Vanlqa® (eflornithine)
  • depilation is performed prior to integumental perturbation. In some embodiments, depilation is performed immediately prior to integumental perturbation. In some embodiments, depilation is performed 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 24 hours, or 2 days prior to integumental perturbation.
  • epilation is performed prior to integumental perturbation. In some embodiments, epilation is performed immediately prior to integumental perturbation. In some embodiments, epilation is performed 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 24 hours, or 2 days prior to integumental perturbation.
  • depilation is not performed prior to integumental perturbation.
  • epilation is not performed prior to integumental perturbation.
  • both depilation and epilation is not performed prior to integumental perturbation.
  • a method of integumental perturbation described herein can be carried out without epilation or depilation.
  • dermabrasion e . g ., using a device with the dermabrasion tip described in Section 5.1.1 herein
  • the skin following integumental perturbation, is not contacted for a period of time with any substance (e . g ., wound dressing, ointment, a bandage, or a device) that is normally administered to an abrasion or wound to promote speed of healing.
  • the skin is not contacted with any substance until, for example, the integumental perturbation has healed ( e . g ., any time between 1 day and 3 weeks).
  • the skin can be contacted with a cast or bandage, e . g ., resulting in increased blood flow to the disrupted skin or decreased transdermal water loss or decreased mass transfer of gases ( e . g . oxygen, carbon dioxide, water vapor) into the skin and/or from the skin, decreased heat transfer from the skin ( e . g . resulting in an increased temperature of the skin surface), or increased pressure on the skin.
  • gases e . g . oxygen, carbon dioxide, water vapor
  • the integumental perturbation is administered in combination with a treatment that reduces scarring, e . g ., surgical scarring, which may be accomplished by placement of elective incisions parallel to the natural lines of skin tension (Langer's lines) or by applying sutures in a "zigzag" pattern, or other methods known in the art.
  • the integumental perturbation is administered in combination with a treatment of wounds (e.g., surgical wounds) that minimizes scarring, by, for example, administering physical therapy to a subject, reducing infection, reducing separation of wound edges, minimizing collagen synthesis, deposition, or accumulation or otherwise causing the process of healing by secondary intention to better resemble healing by primary intention.
  • interventions may be administered prior to, concurrent with, or following the integumental perturbation, and can be used with a treatment of integumental perturbation or as part of or in combination with another treatment described in Section 5.2-5.4 or elsewhere herein or otherwise known in the art.
  • a post-perturbation treatment can be administered one time, or multiple times at intervals of time.
  • the post-perturbation treatment is administered one time per day, or two times per day, or three times per day, or one time or more per week.
  • the precise dosage and duration of treatment may vary with the type of treatment, and the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • a post-perturbation treatment is administered to an area of the skin that has not yet been subjected to integumental perturbation. In some embodiments, a post-perturbation treatment is administered prior to integumental perturbation. In some embodiments, a post-perturbation treatment is administered prior to integumental perturbation and administration of the post-perturbation treatment is stopped during integumental perturbation treatment. In a specific embodiment, administration of the post-perturbation treatment is resumed after integumental perturbation treatment. In some embodiments, a post-perturbation treatment is administered prior to integumental perturbation and administration of the post-perturbation treatment is continued during and after integumental perturbation treatment.
  • a post-perturbation treatment is administered concurrently with integumental perturbation. In some embodiments, a post-perturbation treatment is administered to an area of the skin that has already been subjected to integumental perturbation. In some embodiments, a post-perturbation treatment is administered immediately after integumental perturbation.
  • a post-perturbation treatment is administered immediately prior to integumental perturbation. In some embodiments, a post-perturbation treatment is administered within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 1 month prior to integumental perturbation.
  • a post-perturbation treatment is administered within 5 minutes of integumental perturbation, or 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 24 hours, or 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 1 month or more after integumental.
  • the treatment is continued for 1 day, or for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or more following integumental perturbation. In some embodiments, following commencement of the post-perturbation treatment, the treatment is continued for 3 weeks, 4 weeks, 1 month, or 2, 3, 4, 5, or 6 months, or more following integumental perturbation. In some embodiments, following commencement of the post-perturbation treatment, the treatment is continued for 1 year or more following integumental perturbation.
  • integumental perturbation is followed by a period of 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 1 day, or 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days without the post-perturbation treatment.
  • the integumental perturbation and the post-perturbation treatment are administered less than 1 day apart, at about 1 day apart, 2 days apart, 3 days apart, 4 days apart, 5 days apart, 6 days apart, 7 days apart, 8 days apart 9 days apart, 10 days apart, 11, days apart, 12 days apart, 13 days apart, 14 days apart, or no more than 2 weeks apart.
  • the integumental perturbation and the post-perturbation treatment are administered 2 to 4 days apart, 4 to 6 days apart, 1 week apart, 1 to 2 weeks apart, 2 to 4 weeks apart, one month apart, 1 to 2 months apart, 2 to 3 months apart, 3 to 4 months apart, 6 months apart, or one year or more apart.
  • the integumental perturbation and the post-perturbation treatment are administered within the same patient visit.
  • the integumental perturbation and the post-perturbation treatment are cyclically administered to a subject. Cycling treatment involves the administration of the integumental perturbation one time or for a period of time, followed by the administration of the post-perturbation treatment one time or for a period of time and repeating this sequential administration.
  • the first treatment may be with the integumental perturbation or with the post-perturbation treatment, depending on the subject's prior treatment history and the intended outcome.
  • the integumental perturbation and the post-perturbation treatment are alternately administered in a cycle of 2 years or less, once every 1 year, once every 6 months, once every 3 months, once every 2 months, or once every month.
  • the post-perturbation treatment is administered at the time of integumental perturbation and then maintained for 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 days or longer thereafter (in some embodiments, a scab forms during this time). In some embodiments, a post-perturbation treatment is administered as soon as the scab falls off and maintained for 3 or 4 or 5 days or longer. In one embodiment, the post-perturbation treatment is administered at the time of integumental perturbation and then maintained for 7 or 10 or 12 or 14 days thereafter (in some embodiments, a scab forms during this time).
  • a post-perturbation treatment is administered as soon as the scab falls off and maintained for 7 or 10 or 12 or 14 days. In one embodiment, the post-perturbation treatment is administered at the time of integumental perturbation and then maintained for 19 or 21 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, a post-perturbation treatment is administered as soon as the scab falls off and maintained for 19 or 21 days. In one embodiment, the post-perturbation treatment is administered at the time of integumental perturbation and then maintained for 1 month, 2 months, 3 months, up to 6 months, or up to 1 year or longer thereafter. In some embodiments, a post-perturbation treatment is administered as soon as the scab falls off and maintained 1 month, 2 months, 3 months, up to 6 months, or up to 1 year or longer thereafter.
  • a post-perturbation treatment is combined with a form of integumental perturbation that does not lead to formation of a scab.
  • the post-perturbation treatment is administered before integumental perturbation.
  • the post-perturbation treatment is administered at the time of integumental perturbation.
  • post-perturbation treatment is administered following integumental perturbation.
  • the post-perturbation treatment is administered following integumental perturbation that does not lead to formation of a scab
  • the post-perturbation treatment is administered within 15 minutes of, or 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, 2 weeks, or 3 weeks after integumental perturbation.
  • the post-perturbation treatment is administered following integumental perturbation that does not lead to formation of a scab
  • the post-perturbation treatment is administered within 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or 1 year or more after integumental perturbation.
  • the post-perturbation treatment in which a post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab, is administered before scab formation. In one embodiment, in which a post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab, the post-perturbation treatment is administered during scab formation. In one embodiment, in which post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab, the post-perturbation treatment is administered periscab detachment.
  • the post-perturbation treatment in which a post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab, is administered immediately after scab detachment. In one embodiment, in which post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab, the post-perturbation treatment is administered 1 hour after scab detachment. In one embodiment, in which a post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab, the post-perturbation treatment is administered up to 6 hours after scab detachment.
  • the post-perturbation treatment in which a post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab, is administered 6-12 hours after scab detachment. In one embodiment, in which a post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab, the post-perturbation treatment is administered 12-18 hours after scab detachment. In one embodiment, in which a post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab, the post-perturbation treatment is administered 18-24 hours after scab detachment.
  • the post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab
  • the post-perturbation treatment is administered 1 day, 2 days, 3 days, 4 days 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, or 4 weeks, one month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, I months, or 12 months after integumental perturbation.
  • the post-perturbation treatment is administered following a form of integumental perturbation that leads to formation of a scab
  • the post-perturbation treatment is administered 2 months, 3 months, 4 months, 5 months, 6 months, or 1 year or more after integumental perturbation.
  • a post-perturbation treatment can be administered one time, or repeatedly, in combination with integumental perturbation.
  • a post-perturbation treatment does not include an active pharmaceutical ingredient.
  • a post-perturbation treatment is a hydrogel that does not include an active pharmaceutical ingredient.
  • a post-perturbation treatment is administered at intervals of time, optionally alternating with integumental perturbation treatments also administered at intervals of time.
  • the post-perturbation treatment can be administered one or more times in a controlled release form, which can deliver drug ( e . g ., as described in Section 5.4 supra) in a regimen similar to multiple separate administrations.
  • the present invention comprises integumental perturbation in combination with an additional treatment, wherein the additional treatment may or may not include an active pharmaceutical ingredient
  • the period of time between treatments is at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days; and in some embodiments not more than 14 days.
  • the time between treatments is one week.
  • the time between treatments with post-perturbation treatment is at least 14 days, 21 days, 28 days, or longer.
  • the post-perturbation treatment is administered in order to modulate the neoepidermis that forms underneath the scab.
  • the post-perturbation treatment is administered at the time of integumental perturbation and is maintained up to some time after scab falls off, for example, between 5 - 14 days following integumental perturbation.
  • the course of treatment with post-perturbation treatment is short, for example, limited to one or a few days just following scab detachment, or even continued only for as long as the scab is still attached.
  • the timing of integumental perturbation and post-perturbation treatment administration is preferably monitored and adjusted so that optimal results are achieved.
  • the timing of integumental perturbation (e . g ., using a method described in Section 5.1 or otherwise known in the art) and administration of post-perturbation treatment is adjusted in order to optimize hair growth.
  • a post-perturbation treatment is administered some time before integumental perturbation, and post-perturbation treatment is resumed again after integumental perturbation (optionally in combination with one of the treatments described in Sections 5.3, 5.4 or elsewhere herein or known in the art).
  • a post-perturbation treatment is administered (optionally in combination with one of the treatments described in Sections 5.3, 5.4 or elsewhere herein or known in the art) together with or shortly after integumental perturbation, for example, is administered directly to integumentally perturbed skin.
  • the treatment is continued even as a treatment with a hair growth-promoting agent is begun. For example, this may be accomplished by administering the two treatments concurrently. This may also be accomplished by administering the hair growth-promoting agent in a formulation that is identical to the pharmaceutical composition for post-perturbation treatment, the only difference being the presence or absence, respectively, of hair growth-promoting agent and/or any required excipients, stabilizers, etc.
  • Treatment with a hair growth-promoting agent can be administered one time, or multiple times at intervals of time.
  • the hair growth-promoting agent treatment is administered one time per day, or two times per day, or three times per day, or one time or more per week.
  • the precise dosage and duration of treatment may vary with the type of treatment, and the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • treatment with a hair growth-promoting agents is in combination with integumental perturbation, or is administered to a subject who has undergone treatment with integumental perturbation.
  • treatments may optionally be combined with a post-perturbation treatment described in Section 5.2 supra, and/or a post-perturbation treatment regimen described in Section 5.6.2 supra.
  • a hair growth-promoting agent is administered prior to integumental perturbation. In some embodiment, a hair growth-promoting agent is administered prior to integumental perturbation and administration of the hair growth-promoting agent is continued during and after integumental perturbation treatment. In some embodiments, a hair growth-promoting agent is administered prior to integumental perturbation and administration of the hair growth-promoting agent is stopped during integumental perturbation treatment. In a specific embodiment, administration of the hair growth-promoting agent is resumed after integumental perturbation treatment.
  • one or more hair growth-promoting agents is administered prior to integumental perturbation. In some embodiments, one or more hair growth-promoting agents is administered within 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, or 6 years prior to integumental perturbation. In some embodiments, one or more hair growth-promoting agents is administered continuously prior to integumental perturbation. In some embodiments, one or more hair growth-promoting agents is administered intermittently prior to integumental perturbation. In some embodiments, two or more hair growth-promoting agents are administered serially prior to integumental perturbation. In some embodiments, two or more hair growth-promoting agents are administered concurrently prior to integumental perturbation.
  • one or more hair growth-promoting agents is administered immediately prior to integumental perturbation.
  • a hair growth-promoting agent is administered within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 1 month prior to integumental perturbation.
  • the hair growth-promoting agent is administered after integumental perturbation. In some embodiments, the hair growth-promoting agent is administered immediately after integumental perturbation. In particular embodiments for topical administration of hair growth-promoting agent(s) to wounded skin, the hair growth-promoting agent is formulated to reduce burning or irritation of the wound site.
  • a hair growth-promoting agent is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 1 month after integumental perturbation.
  • a hair growth-promoting agent is administered about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, or 6 months or more after integumental perturbation.
  • integumental perturbation is followed by a period of 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days or more without the hair growth-promoting agent.
  • the timing of treatment with one or more hair growth-promoting agents can be coordinated with the presence or absence of indicators of hair growth in the skin of an area that was treated with integumental perturbation (optionally in combination with a post-perturbation treatment described herein).
  • the one or more hair growth-promoting agents are administered prior to the appearance of vellus hair in a skin site that was treated with integumental perturbation.
  • the one or more hair growth-promoting agents are administered prior to the appearance of new vellus hair in a skin site that was treated with integumental perturbation.
  • the one or more hair growth-promoting agents are administered following the appearance of new vellus hair in a skin site that was treated with integumental perturbation. In some embodiments, the one or more hair growth-promoting agents are administered following the appearance of vellus hair in a skin site that was treated with integumental perturbation. In some embodiments, the one or more hair growth-promoting agents are administered prior to the appearance of terminal hair in a skin site that was treated with integumental perturbation. In some embodiments, the one or more hair growth-promoting agents are administered following the appearance of terminal hair in a skin site that was treated with integumental perturbation.
  • the one or more hair growth-promoting agents are administered following the appearance of terminal hair, and before the terminal-to-vellus hair transition, in a skin site that was treated with integumental perturbation. In some embodiments, the one or more hair growth-promoting agents are administered prior to the appearance of NL, PEL, and/or PELA follicular structures in a skin site that was treated with integumental perturbation. In some embodiments, the one or more hair growth-promoting agents are administered after the appearance of NL, PEL, and/or PELA follicular structures in a skin site that was treated with integumental perturbation.
  • the integumental perturbation and the hair growth-promoting agent are administered less than 1 day apart, at about 1 day apart, 2 days apart, 3 days apart, 4 days apart, 5 days apart, 6 days apart, 7 days apart, 8 days apart 9 days apart, 10 days apart, 11, days apart, 12 days apart, 13 days apart, 14 days apart, no more than 2 weeks apart.
  • the integumental perturbation and the hair growth-promoting agent are administered 2 to 4 days apart, 4 to 6 days apart, 1 week apart, 1 to 2 weeks apart, 2 to 4 weeks apart, one month apart, 1 to 2 months apart, 2 to 3 months apart, 3 to 4 months apart, 6 months apart, or one year or more apart.
  • the integumental perturbation and the hair growth-promoting agent are administered within the same patient visit.
  • the integumental perturbation and the hair growth-promoting agent treatment are cyclically administered to a subject. Cycling treatment involves the administration of the integumental perturbation for a period of time, followed by the administration of the hair growth-promoting agent for a period of time and repeating this sequential administration.
  • the first treatment may be with the integumental perturbation or with the hair growth-promoting agent, depending on the subject's prior treatment history and the intended outcome.
  • the integumental perturbation and the hair growth-promoting agent treatment are alternately administered in a cycle of 3 weeks or less, once every two weeks, once every 10 days or once every week.
  • the integumental perturbation and the post-perturbation treatment are alternately administered in a cycle of 2 years or less, once every 1 year, once every 6 months, once every 3 months, once every 2 months, or once every month.
  • the hair growth-promoting agent treatment is administered at the time of integumental perturbation and then maintained for 1 or 2 or 3 or 4 or 5 days or longer thereafter (in some embodiments, a scab forms during this time). In some embodiments, a hair growth-promoting agent treatment is administered as soon as the scab falls off and maintained for 3 or 4 or 5 days or longer. In one embodiment, the hair growth-promoting agent treatment is administered at the time of integumental perturbation and then maintained for 7 or 10 or 12 or 14 days or longer thereafter (in some embodiments, a scab forms during this time). In some embodiments, a hair growth-promoting agent treatment is administered as soon as the scab falls off and maintained for 7 or 10 or 12 or 14 days or longer.
  • the hair growth-promoting agent treatment is administered at the time of integumental perturbation and then maintained for 19 or 21 days or longer thereafter (in some embodiments, a scab forms during this time). In some embodiments, a hair growth-promoting agent treatment is administered as soon as the scab falls off and maintained for 19 or 21 days or longer. In one embodiment, the hair growth-promoting agent treatment is administered at the time of integumental perturbation and then maintained for 1 month, 2 months, 3 months, up to 6 months, or up to 1 year or longer thereafter. In some embodiments, a hair growth-promoting agent treatment is administered as soon as the scab falls off and maintained 1 month, 2 months, 3 months, up to 6 months, or up to 1 year or longer thereafter.
  • a hair growth-promoting agent treatment is combined with a form of integumental perturbation that does not lead to formation of a scab.
  • the hair growth-promoting agent treatment is administered before integumental perturbation.
  • the hair growth-promoting agent treatment is administered at the time of integumental perturbation.
  • a hair growth-promoting agent treatment is administered following integumental perturbation.
  • the hair growth-promoting agent treatment in which a hair growth-promoting agent treatment is administered following integumental perturbation that does not lead to formation of a scab, is administered within 15 minutes of, or 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, 2 weeks, or 3 weeks after integumental perturbation. In other embodiments, in which a hair growth-promoting agent treatment is administered following integumental perturbation that does not lead to formation of a scab, the hair growth-promoting agent treatment is administered within 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or 1 year or more after integumental perturbation.
  • a hair growth-promoting agent treatment in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, the hair growth-promoting agent treatment is administered before scab formation. In one embodiment, in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, the hair growth-promoting agent treatment is administered during scab formation. In one embodiment, in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, the hair growth-promoting agent treatment is administered periscab detachment.
  • a hair growth-promoting agent treatment in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, the hair growth-promoting agent treatment is administered immediately after scab detachment. In one embodiment, in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, the hair growth-promoting agent treatment is administered 1 hour after scab detachment. In one embodiment, in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, the hair growth-promoting agent treatment is administered up to 6 hours after scab detachment.
  • the hair growth-promoting agent treatment in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, is administered 6-12 hours after scab detachment. In one embodiment, in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, the hair growth-promoting agent treatment is administered 12-18 hours after scab detachment. In one embodiment, in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, the hair growth-promoting agent treatment is administered 18-24 hours after scab detachment.
  • the hair growth-promoting agent treatment in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, is administered 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, 2 weeks, 3 weeks, or 4 weeks after integumental perturbation. In one embodiment, in which a hair growth-promoting agent treatment is administered following a form of integumental perturbation that leads to formation of a scab, the hair growth-promoting agent treatment is administered 2 months, 3 months, 4 months, 5 months, 6 months, or 1 year or more after integumental perturbation.
  • a hair growth-promoting agent treatment can be administered one time, or repeatedly, in combination with integumental perturbation.
  • a hair growth-promoting agent treatment is administered at intervals of time, optionally alternating with integumental perturbation treatments also administered at intervals of time.
  • the hair growth-promoting agent can be administered one or more time in a controlled release form, which can deliver drug in a regimen similar to multiple separate administrations.
  • the period of time between treatments is at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days; and in some embodiments not more than 14 days.
  • the time between treatments is one week.
  • the time between treatments with hair growth-promoting agent is least 14 days, 21 days, 28 days, or longer.
  • the period of time between treatments is at least one month, 3 months, 6 months, 9 months, 12 months, 2 years, 3 years ,4, years, 5 years, 6 years, 7 years or longer.
  • the hair growth-promoting agent treatment is administered in order to modulate the neoepidermis that forms underneath the scab.
  • the hair growth-promoting agent treatment is administered at the time of integumental perturbation and is maintained up to some time after scab falls off, for example, between 5 - 14 days following integumental perturbation.
  • the course of treatment with hair growth-promoting agent is short, for example, limited to one or a few days just following scab detachment, or even continued only for as long as the scab is still attached.
  • the timing of integumental perturbation and hair growth-promoting agent administration is preferably monitored and adjusted so that optimal results are achieved.
  • the timing of integumental perturbation (e . g ., using a method described in Section 5.1 or otherwise known in the art) and administration of hair growth-promoting agent is adjusted in order to optimize hair growth.
  • a hair growth-promoting agent is administered some time before integumental perturbation, and treatment with the hair growth promoting agent is resumed again after integumental perturbation (optionally in combination with one of the treatments described in Sections 5.2, 5.4 or elsewhere herein or known in the art).
  • a hair growth-promoting agent is administered (optionally in combination with one of the treatments described in Sections 5.2, 5.4 or elsewhere herein or known in the art) together with or shortly after integumental perturbation, for example, is administered directly to integumentally perturbed skin.
  • a hair growth-promoting agent is administered (optionally in combination with one of the treatments described in Sections 5.2, 5.4 or elsewhere herein or known in the art) following the new appearance of vellus hair on an area of skin that has been subjected to integumental perturbation.
  • a hair growth-promoting agent is administered (optionally in combination with one of the treatments described in Sections 5.2, 5.4 or elsewhere herein or known in the art) following the appearance of new visually-detectable hair on an area of skin that has been subjected to integumental perturbation.
  • a hair growth-promoting agent is administered (optionally in combination with one of the treatments described in Sections 5.2, 5.4 or elsewhere herein or known in the art) following the appearance of new photographically-detectable hair on an area of skin that has been subjected to integumental perturbation.
  • a hair growth-promoting agent is administered (optionally in combination with one of the treatments described in Sections 5.2, 5.4 or elsewhere herein or known in the art) following the appearance of new terminal hair on an area of skin that has been subjected to integumental perturbation.
  • treatment with hair growth-promoting agent is performed using a formulation as described in Section 5.2 above.
  • treatment with hair growth-promoting agent is commenced on the same day as the integumental perturbation and is continued once, twice, three times, four times, or five times daily for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days.
  • the treatment upon commencement with treatment with the hair growth-promoting agent, is continued once, twice, three times, four times, or five times daily for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days.
  • the treatment upon commencement with treatment with the hair growth-promoting agent, the treatment is continued once, twice, three times, four times, or five times daily for one month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 year, 12 years, 13 years, or indefinitely.
  • the one or more hair growth-promoting agents may be administered in combination with any additional treatment(s) described or incorporated by reference herein ( see , e . g ., Section 5.4 above) or determined to be appropriate by the medical practitioner.
  • the amount of an additional treatment(s) will depend on the desired effect and the additional compound that is selected. Dosages and regimens for administering such additional treatment(s) are the dosages and regimens commonly in use, which can be easily determined by consulting, for example, product labels or physicians' guides, such as the Physicians' Desk Reference (“PDR”) ( e . g ., 63rd edition, 2009, Montvale, NJ: Physicians' Desk Reference ).
  • PDR Physicians' Desk Reference
  • the one or more hair growth-promoting agents may be administered concurrently with or separately from the additional compound(s), or may be administered and/or delivered to the tissue site with different pharmacokinetics.
  • the combination treatment comprises one or more hair growth-promoting agents and an additional compound(s) formulated together.
  • the hair growth-promoting agent in such formulations may be released concurrently with or separately from the additional compound(s), or may be released and/or delivered to the tissue site with different pharmacokinetics.
  • one or more of the compounds in the formulation undergoes controlled release, whereas one or more of the other compounds does not.
  • one or more of the compounds in the formulation undergoes sustained release whereas one or more of the other compounds undergoes delayed release.
  • the combination treatment comprises one or more hair growth-promoting agents and an additional compound(s) formulated separately.
  • the separate formulations may be administered concurrently, sequentially, or in alternating sequence.
  • the one or more hair growth-promoting agents may be administered sequentially, or concurrently with another compound such as finasteride or minoxidil, to achieve the desired effect of hair retention and growth.
  • treatment with one or more hair growth-promoting agents in combination with integumental perturbation prevents, delays, or reverses scalp hair loss in MPHL, FPHL, and/or diffuse hair thinning associated with aging.
  • treatment with integumental perturbation (with or without a post-perturbation treatment) prior to treatment with one or more hair growth-promoting agents improves the effectiveness of the hair growth-promoting agent, making the treatment more effective, efficient, cost-effective, and/or user friendly.
  • the efficacy of the agent may be increased.
  • one of the treatments on its own is not cosmetically satisfactory, the benefits are too short-lived, or the hair that results from the treatment is vellus hair, or other thin or patchy hair, or has inadequate pigmentation.
  • the hair that results may be more cosmetically satisfactory, longer lasting, thicker, more uniform, and properly pigmented hair, terminal hair or scalp hair as opposed to vellus hair inferior in such attributes.
  • more than one hair will emerge from each follicle, leading to the appearance of thicker hair.
  • Integumental perturbation is achieved by either treatment with a fractional erbium-YAG laser to epidermal or dermal depth, a fractional CO 2 laser to epidermal or dermal depth, or dermabrasion to epidermal or dermal depth as described herein. This is followed by treatment with one or more of the following hair growth-promoting agents: estrogen, finasteride, or dutasteride (AvodartTM).
  • This treatment causes follicles (or Follicle Stem Cells) to be stimulated, activated, or reprogrammed, e.g., a miniaturizing male temporal scalp follicle (or Follicle Stem Cell) is changed to a non-miniaturizing female-type temporal scalp follicle (or Follicle Stem Cell). Then, optionally, terminal hair growth is further stimulated by the application of minoxidil, bimatoprost, or latanoprost. Alternatively, in this embodiment the follicle type can be stimulated, activated, or reprogrammed, e .
  • a miniaturizing male temporal scalp follicle can be changed to a non-miniaturizing male occipital scalp-type follicle.
  • terminal hair growth is stimulated by the application of finasteride, dutasteride, minoxidil, bimatoprost, or latanoprost.
  • integumental perturbation is achieved by either treatment with a fractional erbium-YAG laser to epidermal or dermal depth, a fractional CO 2 laser to epidermal or dermal depth, or dermabrasion to epidermal or dermal depth as described herein.
  • This treatment causes follicles to be stimulated, activated, or reorganized and/or or Follicle Stem Cells to form new follicles, which are receptive to the effects of hair growth-promoting agents, such as finasteride, dutasteride, minoxidil, bimatoprost, or latanoprost. Stimulation of the reorganized and/or new follicles by such agents then results in increased numbers of terminal hairs.
  • hair growth-promoting agents such as finasteride, dutasteride, minoxidil, bimatoprost, or latanoprost.
  • the combination of integumental perturbation and treatment with one or more hair growth-promoting agents of an area of skin that already contains hair-producing follicles increases production of hair in that area of skin.
  • the combination of integumental perturbation and hair growth-promoting agent treatment is administered to skin that has been damaged and which no longer contains follicles.
  • the combination of integumental perturbation and hair growth-promoting agent treatment may restore follicle production in that area of skin.
  • a combination treatment of integumental perturbation and one or more hair growth-promoting agents in order to restore hair follicles and/or growth to that area of skin.
  • These effects may be accomplished by modulating the dosage of the one or more hair growth-promoting agents.
  • Synergism occurs when the combination has an effect that is more than would be expected from merely the additive effect of each element in the combination, for example, if branched hair follicles or multiple shafts per pore were produced by the combination and not by either alone.
  • This section provides an exemplary method to induce hair growth on the scalp. More specifically, provided herein is a method to induce hair growth on the scalp of a male or female subject with androgenetic alopecia. Even more specifically, provided herein is a method to induce hair growth on the scalp of a male or female subject having androgenetic alopecia with the presence of a vertex transition zone defined as an area possessing both terminal and miniaturized hairs, Hamilton-Norwood type 3V, 4, 5, 5A, or 5V, and Fitzpatrick skin type 1-4.
  • the method for inducing hair growth comprises: (a) integumental perturbation; (b) an optional period of treatment with a post-perturbation treatment described in Section 5.2 supra ; and (c) an optional period of treatment with minoxidil. More specifically, the method for inducing hair growth comprises in the following order: (a) integumental perturbation; (b) a period of treatment with a post-perturbation treatment described in Section 5.2 supra ; (c) a period without treatment; and (d) a period of treatment with minoxidil.
  • controlled integumental perturbation using dermabrasion results in neogenic-like hair follicles, and/or stimulated, activated or reorganized pre-existing hair follicles; and the subsequent treatment of the induced neogenic-like follicles, and/or stimulated, activated or reorganized pre-existing hair follicles, with minoxidil or other hair growth-promoting agent(s) results in more numerous, longer lasting, and/or thicker hair shafts.
  • treatment with minoxidil or other hair growth-promoting agent(s) prior to controlled integumental perturbation results in more numerous, longer lasting, and/or thicker hair shafts.
  • treatment with the optional post-perturbation treatment is commenced on the same day as the integumental perturbation and is continued once, twice, three times, four times, or five times daily for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days.
  • integumental perturbation is followed by a period of zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days without topical treatment ( e .
  • treatment with minoxidil is commenced wherein minoxidil is applied once, twice, three times, four times, or five times daily for at least 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 month, 7 months, 8 months, 9 months or at least 10 months.
  • 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, or 8% topical minoxidil can be used ( e . g ., ROGAINE).
  • treatment with minoxidil can be combined with another treatment as described elsewhere in Section 5.3 above and in Section 5.4 below, or administered with a drug delivery device, for example, described in Section 5.3.1.
  • the method for inducing hair growth further comprises administration of finasteride (PROPECIA).
  • finasteride can be administered orally at a dose of 1 mg/day.
  • administration of finasteride commences concurrently with the topical treatment with minoxidil.
  • the method for inducing hair growth further comprises administration of dutasteride or any other 5-alpha-reductase inhibitor known to the skilled artisan.
  • dutasteride can be administered orally at a dose of 0.05 mg/day, 0.1 mg/day, 0.5 mg/day, or 2.5 mg/day,.
  • administration of dutasteride commences concurrently with the topical treatment with minoxidil.
  • a method for inducing hair growth on the scalp of a male or female subject with androgenetic alopecia comprises:
  • a method for inducing hair growth on the scalp of a male or female subject with androgenetic alopecia comprises:
  • a method for inducing hair growth on the scalp of a male or female subject with androgenetic alopecia comprises:
  • the present invention provides a kit comprising in separate containers hydrogel and topical minoxidil.
  • the minoxidil can be 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, or 8% topical minoxidil ( e . g ., ROGAINE).
  • the kit further comprises means for integumental perturbation ( e . g ., a handheld dermabrasion device).
  • detectable hairs can be quantified by photography, e.g., by global photographic recording or phototrichographic analysis (as described in, e.g., Uno et al., 2002, Acta Venereol 82:7-12 , incorporated herein by reference) or assessed visually e.g. by a rating scale (as described in Kaufman et al. J Amer Acad Dermatol 1998; 39: 578-89 . Further, changes in the hair shaft thickness of photographically detectable hairs can be determined. Further, the permanence of the hair growth is monitored over a time period of at least 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 4 years, or at least 5 years.
  • topical latanoprost can be used.
  • 0.01%, 0.03%, 0.05% or 0.1% topical bimatoprost can be used.
  • 0.0005%, 0.0015%, 0.005%, or 0.05% topical tafluprost can be used.
  • 0.00013%, 0.00033%, 0.001%, 0. 0.00267%, 0.004%, or 0.01% topical travoprost can be used.
  • Human hair patterning consists of gender specific changes that occur over the life of subjects and vary in degree between individuals and more generally between humans of different racial and ethnic backgrounds.
  • males and females Before puberty, males and females have similar patterns of scalp hair and the rest of their bodies are covered with largely invisible vellus hair.
  • the forearms and legs grow thin, fine terminal hair gradually even before puberty.
  • puberty In males and females puberty is associated with terminal hair growth in the axilla, and anogenital regions.
  • both males and females grow terminal hair over forearms and legs, but males have quantitatively more growth in these regions.
  • Males after puberty grow terminal hair over the moustache/beard, chest, and back regions.
  • Sex hormones are synthesized by the skin locally where they exert intracrine or paracrine actions.
  • each sex steroid depends upon the activity of androgen- and estrogen-synthesizing enzymes and of appropriate androgen- and estrogen receptors in specific cell types. Androgens are regulated by five major enzymes and changes in the expression of isoenzymes; or changes in the expression of androgen receptor and androgen receptor transactivating factors regulate hair patterning.
  • Estrogens are produced in sebaceous glands which express cytochrome P450 aromatase ("aromatase”) that converts androgen to 17-beta-estradiol (E2).
  • Estrogens act on Estrogen Receptor alpha (ERalpha) and Estrogen Receptor alpha (ERbeta) in human skin are expressed in site specific localizations.
  • androgens In addition to regulating hair patterning and growth, androgens have effects in sebaceous gland growth and differentiation, epidermal barrier homeostasis and wound healing; and estrogens regulate skin aging, pigmentation, hair growth, sebum production and skin cancer. ( Ohnemus et al., 2006, Endocr Rev. 27(6):677-706 , "The hair follicle as an estrogen target and source.")
  • any stage of the Ludwig classification for female pattern hair loss can be treated by the methods and treatments described herein.
  • the Ludwig Classification uses three stages to describe female pattern genetic hair loss: Type I (mild), Type II (moderate), Type III (extensive). In all three Ludwig stages, there is hair loss on the front and top of the scalp with relative preservation of the frontal hairline. The back and sides may or may not be involved. Regardless of the extent of hair loss, only women with stable hair on the back and sides of the scalp are candidates for hair transplant surgery.
  • the treatments described herein can be used to treat Type 1, Type II and/or Type III stages of the Ludwig classification for female pattern genetic hair loss.
  • any stage of the Savin scale for female pattern hair loss can be treated by the methods and treatments described herein.
  • stage I-1 there is no hair loss.
  • stages I-2, I-3, I-4 of the Savin scale the width of the parting gets progressively wider indicating thinner hair along the center of the scalp.
  • stages II-1 and II-2 of the Savin scale there is diffuse thinning of the hair over the top of the scalp.
  • stage III of the Savin scale there is extensive diffuse hair loss on top of the scalp, but some hair does survive.
  • the "advanced" stage of the Savin scale there is extensive hair loss and little to no surviving hair in the alopecia affected area.
  • any stage of the Savin scale for female pattern hair loss can be treated by the methods and treatments described herein.
  • the Olsen scale grades female hair loss into 3 stages based on a frontal accentuation pattern in which the hair loss is more profound in the frontal region that gradually tapers back toward less hair loss in the occipital when viewed with a central hair part.
  • stage 1 of the Olsen scale there is mild to moderate frontal accentuation loss.
  • stage 2 of the Olsen scale there is both frontal accentuation that can be more severe than in stage 1 and mixed with diffuse hair loss.
  • stage 3 of the Olsen scale the loss is so severe that only diffuse thinning is principally noted.
  • a candidate subject for treatment with one or more methods described herein is any subject suffering from hair loss, hair thinning, balding, or who has or has had a disease or condition associated therewith, or who wishes to enhance the growth or thickness of hair.
  • the subject may be any subject, preferably a human subject, including male, female, intermediate/ambiguous (e.g., XO), and transsexual subjects.
  • the subject is a human adolescent.
  • the subject is undergoing puberty.
  • the subject is a middle-aged adult.
  • the subject is a premenopausal adult.
  • the subject is undergoing menopause.
  • the subject is elderly.
  • the subject is a human of 1 year old or less, 2 years old or less, 2 years old, 5 years old, 5 to 10 years old, 10 to 15 years old, e.g ., 12 years old, 15 to 20 years old, 20 to 25 years old, 25 to 30 years old, 30 years old or older, 30 to 35 years old, 35 years old or older, 35 to 40 years old, 40 years old or older, 40 to 45 years old, 45 to 50 years old, 50 years old or older, 50 to 55 years old, 55 to 60 years old, 60 years old or older, 60 to 65 years old, e.g ., 65 years old, 65 to 70 years old, 70 to 75 years old, 75 to 80 years old, 80 to 85 years old, 85 to 90 years old, 90 to 95 years old or 95 years old or older.
  • the subject is a male 20 to 50 years old. In some embodiments, the subject is a male 20 to 60 years old. In some embodiments, the subject is a male 30 to 60 years old. In some embodiments, the subject is a male 40 to 60 years old. In some embodiments, the subject is a male or female 12 to 40 years old. In some embodiments, the subject is not a female subject. In some embodiments, the subject is not pregnant or expecting to become pregnant. In some embodiments, the subject is not a pregnant female in the first trimester of pregnancy. In some embodiments, the subject is not breastfeeding.
  • the treatment is delivered to an area in which hair growth is desired, for example, the scalp, the face (e . g ., the eyebrow, eyelashes, upper lip, lower lip, chin, cheeks, beard area, or mustache area), or another part of the body, such as, e.g ., the chest, abdomen, arms, armpits (site of axillary hair), legs, or genitals.
  • treatment is delivered to the head.
  • treatment is delivered to the scalp.
  • treatment is delivered to a balding scalp.
  • treatment is not delivered to the face.
  • treatment is not delivered to an area of the skin that is normally covered with only, or mostly, vellus hair.
  • hair restoration to a wounded or scarred part of the skin is desired.
  • the scar is caused by surgery, such as a face lift, skin graft, or hair transplant.
  • the subject may have a disease or disorder of balding or hair loss (including hair thinning), such as forms of nonscarring (noncicatricial) alopecia, such as androgenetic alopecia (AGA), including MPHL or FPHL ( e .
  • a disease or disorder of balding or hair loss including hair thinning
  • forms of nonscarring (noncicatricial) alopecia such as androgenetic alopecia (AGA), including MPHL or FPHL ( e .
  • thinning of the hair i.e., diffuse hair loss in the frontal/parietal scalp
  • any other form of hair loss caused by androgens toxic alopecia, alopecia areata (including alopecia universalis), scarring (cicatricial) alopecia, pathologic alopecia (caused by, e.g., medication, trauma stress, autoimmune diseases, malnutrition, or endocrine dysfunction), trichotillomania, a form of hypotrichosis, such as congenital hypotrichosis, or lichen planopilaris, or any other condition of hair loss or balding known in the art or described infra.
  • the subject has hair loss caused by a genetic or hereditary disease or disorder, such as androgenetic alopecia.
  • the subject has hair loss caused by anagen effluvium, such as occurs during chemotherapy (with, e.g ., 5-fluorouracil, methotrexate, cyclophosphamide, vincristine).
  • anagen effluvium such as occurs during chemotherapy (with, e.g ., 5-fluorouracil, methotrexate, cyclophosphamide, vincristine).
  • Anagen effluvium can be caused by other toxins, radiation exposure (including radiation overdose), endocrine diseases, trauma, pressure, and certain diseases, such as alopecia areata (an autoimmune disease that attacks anagen follicles.)
  • the subject has hair loss caused by telogen effluvium.
  • Telogen effluvium is caused frequently by drugs like lithium and other drugs like valproic acid and carbamazepine.
  • telogen effluvium can be induced by childbirth, traction, febrile illnesses, surgery, stress, or poor nutrition. (See, Mercke et al., 2000, Ann. Clin. Psych. 12:35-42 ).
  • the subject has hair loss caused by or associated with medication, such as chemotherapy (e . g ., anti-cancer therapy or cytotoxic drugs), thallium compounds, vitamins ( e . g ., vitamin A), retinoids, anti-viral therapy, or psychological therapy, radiation (such as the banding pattern of scalp hair loss that may be caused by radiation overdose), trauma, endocrine dysfunction, surgery, physical trauma, x-ray atrophy, burning or other injury or wound, stress, aging, an autoimmune disease or disorder, malnutrition, an infection (such as, e.g., a fungal, viral, or bacterial infection, including chronic deep bacterial or fungal infections), dermatitis, psoriasis, eczema, pregnancy, allergy, a severe illness ( e .
  • medication such as chemotherapy (e . g ., anti-cancer therapy or cytotoxic drugs), thallium compounds, vitamins ( e . g ., vitamin A), retinoids, anti-
  • the subject has hair thinning, or "shock loss,” or a bald patch caused by prior use as a source of tissue or follicles for hair transplantation or follicular unit transplantation.
  • a candidate subject is a subject who wishes to enhance hair growth, for example, to have more hair, faster-growing hair, longer hair, and/or thicker hair.
  • the candidate is a subject who wishes to increase hair pigmentation.
  • the subject is not affected by a condition of excessive hair loss.
  • the subject has scarring (cicatricial) alopecia.
  • forms of cicatricial alopecia that may be treated in accordance with the methods described herein include primary cicatricial alopecia (PCA) and secondary cicatricial alopecia.
  • Primary cicatricial alopecias that may be treated in accordance with the methods described herein include lymphocyte-mediated PCAs, such as lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA), and pseudopelade (Brocq); neutrophil-mediated PCAs, such as folliculitis decalvans and tufted folliculitis; and PCAs involving a mixed inflammatory infiltrate, such as occurs in dissecting cellulitis and folliculitis keloidalis.
  • lymphocyte-mediated PCAs such as lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA), and pseudopelade (Brocq)
  • neutrophil-mediated PCAs such as folliculitis decalvans and tufted folliculitis
  • a candidate subject for treatment in a candidate subject for treatment, the area affected by the scarring alopecia is no longer increasing. In some embodiments, in a candidate subject for treatment, hair loss has in the affected area has ceased. In some embodiments, a candidate subject for treatment is clinically quiescent with respect to the inflammatory activity that may be associated with the condition. In one embodiment with respect to a subject having a lymphocyte-mediated PCA, inflammation is measured as the number of T lymphocytes and/or T lymphocyte subsets as detected in lesional skin, e.g., by immunoperoxidase cell surface staining using monoclonal antibodies.
  • lymphocytic inflammation (which may be found along with necrotic keratinocytes) is detected by histologic examination of the scalp.
  • direct immunofluorescence staining techniques are employed to detect antibody deposits in the affected tissue.
  • clinical evaluation of the scalp is performed to determine clinical quiescence of the inflammation. Symptoms of itching, burning, pain, or tenderness usually signal ongoing activity. Signs of scalp inflammation include redness, scaling, and pustules.
  • a scalp biopsy can be performed to demonstrate active inflammation or its absence.
  • a hair "pull test” is performed to identify areas of active disease in which follicles are easily pulled out, and thus, inflammation is still ongoing.
  • the pulled hairs can be mounted on a slide and the hair bulbs are viewed with a microscope to determine how many are growing hairs and how many are resting hairs.
  • cultures may be performed to identify which microbes, if any, may be contributing to the inflammation.
  • a subject is clinically quiescent if hairs cannot be easily pulled out, if itching, burning, pain, tenderness, redness, scaling, and / or pustules are absent from the affected area.
  • a method described herein is used to enhance hair growth in a patient with scarring alopecia.
  • the patient has a secondary cicatricial alopecia.
  • the patient has a form of primary cicatricial alopecia, such as lymphocyte-mediated PCAs, such as lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA), and pseudopelade (Brocq); neutrophil-mediated PCAs, such as folliculitis decalvans and tufted folliculitis; and PCAs involving a mixed inflammatory infiltrate, such as occurs in dissecting cellulitis and folliculitis keloidalis.
  • lymphocyte-mediated PCAs such as lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA), and pseudopelade (Brocq)
  • Cicatricial alopecias affect both men and women, most commonly adults, although all ages may be affected. In general, they are rare. There have been a few reports of cicatricial alopecia occurring in a family. However, the majority of patients with cicatricial alopecia have no family history of a similar condition. Lichen planopilaris may affect middle-aged women most commonly. Central centrifugal alopecia may affect black women most commonly. Frontal fibrosing alopecia is seen most commonly in post-menopausal women.
  • a candidate subject for treatment for scarring alopecia is a black woman (e.g., of African-American descent), a middle-aged woman, or a post-menopausal woman.
  • the invention provides a method for enhancing hair growth in a patient with scarring alopecia comprising controlled integumental perturbation using a fractional ablative laser, followed by twice daily topical administration of hair growth-promoting agent for 14 days.
  • the hair growth-promoting agent treatment is begun on the same day as the laser treatment.
  • treatment with hair growth-promoting agent is commenced on the same day as the integumental perturbation and is continued once, twice, three times, four times, or five times daily for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days.
  • the invention provides a method for enhancing hair growth in a patient with lichen planopilaris comprising controlled integumental perturbation using a fractional ablative laser, followed by twice daily topical administration of hair growth-promoting agent for 14 days.
  • the hair growth-promoting agent treatment is begun on the same day as the laser treatment.
  • treatment with hair growth-promoting agent is commenced on the same day as the integumental perturbation and is continued once, twice, three times, four times, or five times daily for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days.
  • the invention provides a method for enhancing hair growth in a patient with frontal fibrosing alopecia comprising controlled integumental perturbation using a fractional ablative laser, followed by twice daily topical administration of hair growth-promoting agent for 14 days.
  • the hair growth-promoting agent treatment is begun on the same day as the laser treatment.
  • treatment with hair growth-promoting agent is commenced on the same day as the integumental perturbation and is continued once, twice, three times, four times, or five times daily for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, or 21 days.
  • the following are exemplary combination treatments comprising integumental perturbation and hair growth-promoting agent treatment for enhancing hair growth in a patient having scarring alopecia.
  • the combination treatment is specific for a particular subtype of scarring alopecia.
  • the combination treatment for enhancing hair growth in a patient with scarring alopecia comprises a form of integumental perturbation, such as described in Section 5.1, optionally in combination with a post-perturbation treatment described in Section 5.2, a hair growth-promoting agent treatment such as described in Section 5.3, and/or one or more additional treatments described in Section 5.4 or elsewhere herein or otherwise known in the art.
  • an affected area of the skin is transplanted with hair follicles from an unaffected area.
  • surgical techniques for replacing tissue comprising scarred hair follicles with tissue from another area of the skin (e.g., scalp) comprising unaffected hair follicles are used.
  • Surgical treatment for cosmetic benefit is an option in, for example, some cases after the disease has been inactive for one to two or more years. Hair restoration surgery or scalp reduction may be considered in these instances.
  • the integumental perturbation is a form of scar revision, such as skin graft, serial expansion of surrounding skin, or laser treatment.
  • the integumental perturbation is a form of scar re-excision with subsequent healing by primary intention, treatment with steroids (e.g., corticosteroid injection), silicone scar treatments (e.g., dimethicone silicone gel or silicone sheeting), use of porcine fillers or other cosmetic fillers (e.g., inserted under atrophic scars), ribosomal 6 kinase (RSK) antagonists, antagonists of pro-inflammatory cytokines, such as TGF ⁇ 2 or TNF, osteopontin antagonists, the use of pressure garments, needling, dermabrasion, collagen injections, low-dose radiotherapy, or vitamins (e.g., vitamin E or vitamin C or its esters).
  • steroids e.g., corticosteroid injection
  • silicone scar treatments e.g., dimethicone silicone gel or silicone sheeting
  • porcine fillers or other cosmetic fillers e.g., inserted under atrophic scars
  • RSK ribosomal 6 kin
  • the integumental perturbation for the treatment of scarring alopecia is administered with a procedure that promotes wound healing with reduced scarring, as described in, e.g ., Section 5.1 supra.
  • the combination treatment for a patient with scarring alopecia comprises controlled integumental perturbation using a fractional ablative laser, followed by twice daily topical administration of hair growth-promoting agent for 14 days.
  • the hair growth-promoting agent treatment is begun on the same day as the laser treatment.
  • the patient has primary cicatricial alopecia.
  • the patient has lichen planopilaris or frontal fibrosing alopecia.
  • the combination treatment for enhancing hair growth in a patient having scarring alopecia comprises integumental perturbation, optionally with hair growth-promoting agent treatment, in combination with one or more anti-inflammatory medications and antimalarial drugs.
  • Medications that may be administered orally include hydroxychloroquine, doxycycline, mycophenolate mofetil, cyclosporine, or corticosteroids.
  • Medications that may be administered topically include corticosteroids (such as, e.g., betamethasone, e.g., Luxiq®), tacrolimus, pimecrolimus, or Derma-Smoothe/FS scalp oil.
  • Medications that may be administered by injection include triamcinolone acetonide (a corticosteroid), which may be injected into inflamed, symptomatic areas of the scalp.
  • a corticosteroid triamcinolone acetonide
  • such combinations are used in the treatment of a patient with the lymphocytic group of cicatricial alopecias, including lichen planopilaris, frontal fibrosing alopecia, central centrifugal alopecia, and pseudopelade (Brocq).
  • the combination treatment for enhancing hair growth in a patient having scarring alopecia comprises integumental perturbation, optionally in combination with a hair growth-promoting agent treatment, in combination with one or more antibiotics, such as oral or topical antibiotics.
  • the combination treatment comprises one or more retinoids, such as isotretinoin, or methotrexate, tacrolimus, cyclosporin, or thalidomide.
  • such combinations are used in enhancing hair growth in a patient with the neutrophilic group of cicatricial alopecias (e.g., folliculitis decalvans, tufted folliculitis, and dissecting cellulitis), and successful treatment enhances hair growth while reducing or eliminating microbes that are involved in the inflammatory process.
  • the neutrophilic group of cicatricial alopecias e.g., folliculitis decalvans, tufted folliculitis, and dissecting cellulitis
  • a combination treatment for a patient with the mixed group of cicatricial alopecias may include antimicrobials, isotretinoin, and anti-inflammatory medications.
  • thinning diffuse hair loss in the frontal/parietal scalp.
  • FPHL Male Pattern Hair Loss
  • MPHL a process driven by the androgen, dihydrotestosterone (DHT), which can be inhibited and to some extent reversed by finasteride which inhibits the conversion of testosterone to DHT.
  • DHT dihydrotestosterone
  • finasteride which inhibits the conversion of testosterone to DHT.
  • Minoxidil can also delay or reverse MPHL.
  • MPHL androgenetic alopecia
  • the combination treatments disclosed herein for age-related hair loss comprise a combination of treatment with one or more hair growth-promoting agents and estrogen replacement therapy or androgen inhibition therapy.
  • Interleukin-1 alpha decreases responses to androgen in cultured dermal papilla cells ( Boivin et al., 2006, Exp Dermatol. 15:784-793 ).
  • TGF-betal may mediate androgen-induced hair growth suppression, since in culture, human dermal papilla cells (DPCs) from androgenetic alopecia (AGA) subjects that transiently expressing androgen receptor were co-cultured with keratinocytes (KCs), and secreted TGF-betal that inhibited KC growth ( Inui et al., 2003, J Investig Dermatol Symp Proc. 8:69-71 ).
  • DPCs human dermal papilla cells
  • AGA androgenetic alopecia
  • adjuvants and/or other stimulators of local cytokines are used in conjunction with the treatment with one or more hair growth-promoting agents.
  • one rationale for administering adjuvants and/or other stimulators of local cytokines in conjunction with the treatment with one or more hair growth-promoting agents is that the production of local cytokines may induce changes in the follicle cell cycle and recruit new FSCs to follicles.
  • Melatonin is a protein hormone secreted by the pineal gland modulates hair growth, pigmentation and/or molting in many species. Human scalp hair follicles in anagen are important sites of extra-pineal melatonin synthesis. Melatonin may also regulate hair Follicle Cycle control, since it inhibits estrogen receptor-alpha expression ( Fischer et al., 2008, Pineal Res. 44:1-15 ). These treatments can be administered in combination with the methods described herein.
  • compositions comprising a hair growth-promoting agent or other drug described herein - alone or in combination with integumental perturbation - can be determined by standard pharmaceutical procedures in cell culture or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is known as the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Dosage regimens that exhibit large therapeutic indices are preferred.
  • Data obtained from the in vitro assays and animal studies described herein can be used in formulating a dosage range of the hair growth-promoting agent or other drug described herein for use in human subjects.
  • the dosage of the hair growth-promoting agent or other drug described herein lies preferably within a range of skin concentrations, and possibly circulating concentrations, that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from in vitro (e.g., cell culture) assays or animal assays. Such information can be used to more accurately determine useful doses in human subjects.
  • Levels in whole blood or plasma may be measured, for example, by high performance liquid chromatography or any other method described herein.
  • Levels in skin may be measured, for example, by an LC/MS/MS assay described herein.
  • any assays known to those skilled in the art can be used to evaluate the efficacy of treatment with a hair growth-promoting agent or other drug described herein, either alone or in a combination treatment described herein.
  • Skin explant model The efficacy of the treatments described herein may be tested using skin explants, for example, prepared from skin biopsies or other surgical procedures. See, e.g., Ballanger et al., supra.
  • Human skin equivalents can be grown and assembled in vitro, with the advantage that they can be grown to theoretically to any size/shape; can be comprised of different types of cells, including keratinocytes (hair follicle derived and non-hair follicle derived), dermal cells (hair follicle derived and non-hair follicle derived), other cell types (e.g ., mesenchymal stem cells); can contain cells that are genetically modified to include, e.g ., markers or "inducible" signaling molecules; provide an unlimited and uniform source of human cells; from normal skin based on histology and marker studies; are generally devoid of skin appendages; and can be integumentally perturbed as in vivo.
  • keratinocytes hair follicle derived and non-hair follicle derived
  • dermal cells hair follicle derived and non-hair follicle derived
  • other cell types e.g ., mesenchymal stem cells
  • Human skin and hair have features that are relatively unique among terrestrial mammals.
  • Old World Apes (gorillas and chimpanzees) have areas of skin that lack visible hair; on the face surrounding the eyes, nose and mouth; on ears; and the plantar surfaces of hands and feet.
  • Rhesus Macaque has patterned alopecia in males and females.
  • Gorillas have hair patterning with respect to color on dominant males: i.e., the "Silverback.” While certain of these mechanisms share similarities to humans, the extent and degree of hair patterning in human remains relatively unique.
  • Another animal model for use in evaluating treatment that may more closely mimic the biology of human skin and hair is a guinea pig model ( see , Stenn & Paus, 2001, Physiol. Revs. 81: 449-494 ).
  • the methods for evaluating treatment described herein may be applied to guinea pigs according to methods known in the art. See also, e.g ., Kramer et al., 1990, Dermatol Monatsschr 176:417-20 ; and Simon et al., 1987, Ann Plast Surg 19:519-23 .
  • Other animal models that may be of use in evaluating the treatments described herein include pig ( e.g., Red Duroc), or cat models.
  • Success of treatment aimed at improving hair growth in an animal model can be measured by: improved overall cosmetic outcome; increased hair count; increased hair density; increased thickness of hair or hair shaft (diameter); increased hair weight; hair cuttings; longer hair; increase in the amount of terminal hair; increase in the amount of vellus hair; an increase in the ratio of terminal-to-vellus hair; increase in the amount of nonvellus, e.g ., intermediary or terminal, hair; increased number of hair follicles; increased number of hair follicles at a more mature stage of development; increased numbers of follicular units with 3 or more hair follicles; increased hair follicle branching; formation of new hair follicles ("hair follicle neogenesis"); formation of new hair follicles with vellus-sized hair shafts ( i.e., hair shafts with diameters less than 30 microns in diameter); hair follicle regeneration; increased stimulation or activation of existing hair follicles; increased number of stimulated
  • any method known in the art may be used to evaluate the safety and efficacy of a treatment described herein.
  • a human skin xenograft model is used.
  • one or more hair growth-promoting agents may be administered with a full thickness excision, laser, inflammatory stimulus, or dermabrasion procedure for integumental perturbation described herein.
  • a synergistic effect of an integumental perturbation treatment and treatment with one or more hair growth-promoting agents or another treatment described herein may be measured as an improvement over a control subject receiving only one of the two or more treatments (e.g ., the treatment with integumental perturbation alone, with or without a post-perturbation treatment, with or without one or more hair growth-promoting agents alone).
  • a human skin xenograft (without skin appendages) can be considered as similar to a scar, and can be wounded and then treated pharmacologically to induce hair growth.
  • Xenografts can also be combined with inducible genetically modified cells to activate pathways know to form hair follicles.
  • the safety and efficacy of a treatment described herein is tested in a full thickness or a split thickness human skin xenograft (e.g ., obtained surgically from scar revisions; from foreskin; or cadaveric), or may be tested in a three-dimensional organotypic human skin culture on SCID mice.
  • a split thickness human skin xenograft e.g ., obtained surgically from scar revisions; from foreskin; or cadaveric
  • SCID mice three-dimensional organotypic human skin culture on SCID mice.
  • the safety and efficacy of a treatment described herein may also be measured in human subjects according to methods known in the art. See, e.g ., International Patent Application Publication No. WO 2005/084621, published September 15, 2005 , the contents of which is incorporated by reference herein in its entirety.
  • success of treatment aimed at treating alopecia, treating baldness, or promoting hair growth can be measured according to one or more of the following methods:
  • success of treatment is assessed by examination of hair follicles in a treated area of the subject's skin.
  • hair follicles are examined histologically, or by determination of the presence or absence of certain markers of hair follicle development or morphology.
  • the area of skin for examination may be obtained by biopsy, such as a punch biopsy; alternatively or in addition, in a less invasive method, the skin may be analyzed directly by, e.g ., confocal microscopy or other technique that permits imaging beneath the surface of the skin.
  • success of a treatment method described herein is determined by an increase in the number of hair follicles in a treated area, for example, compared to an untreated control (or compared to baseline before treatment). In one embodiment, success of a treatment method described herein is determined by the presence or increased numbers of neogenic-like (NL) follicles, for example, compared to an untreated control (or compared to baseline before treatment).
  • NL neogenic-like
  • success of a treatment method described herein is determined by the presence or increased numbers of activated or stimulated pre-existing follicles, such as pre-existing like (PEL) or pre-existing-like, attached (PELA) follicular structures, for example, compared to an untreated control (or compared to baseline before treatment).
  • success of a treatment method described herein is determined by the presence or increased numbers of NL, PEL, and/or PELA follicular structures, for example, compared to an untreated control (or compared to baseline before treatment).
  • a treatment regimen described herein increases the number of hair follicles by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment described herein increases the number of hair follicles by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein increases the number of hair follicles by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a treatment with one or more hair growth-promoting agents described herein increases the number of hair follicles by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • a treatment regimen described herein increases the number of activated or stimulated hair follicles (e.g., NL, PEL or PELA follicular structures) by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • activated or stimulated hair follicles e.g., NL, PEL or PELA follicular structures
  • an integumental perturbation treatment described herein increases the number of activated or stimulated hair follicles (e.g., NL, PEL or PELA follicular structures) by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • activated or stimulated hair follicles e.g., NL, PEL or PELA follicular structures
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein increases the number of activated or stimulated hair follicles (e.g., NL, PEL or PELA follicular structures) by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • activated or stimulated hair follicles e.g., NL, PEL or PELA follicular structures
  • an integumental perturbation treatment in combination with a treatment with one or more hair growth-promoting agents described herein increases the number of activated or stimulated hair follicles (e.g., NL, PEL or PELA follicular structures) by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • the increase in number of hair follicles, activated or stimulated hair follicles, and/or NL, PEL, or PELA structures is observed in the treated area, for example, in an area of skin that was treated with integumental perturbation. In other embodiments, the increase in number of hair follicles, activated or stimulated hair follicles, and/or NL, PEL, or PELA structures is observed adjacent to the treated area. In other embodiments, the increase in number of hair follicles, activated or stimulated hair follicles, and/or NL, PEL, or PELA structures is observed in and adjacent to the treated area.
  • measurement of hair follicles in accordance with the foregoing is within 3 days, or 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 3 weeks, 4 weeks, or 1 month or longer after initiation of the treatment regimen.
  • measurement of hair follicles in accordance with the foregoing is based on a skin biopsy taken within 3 days, or 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 3 weeks, 4 weeks, or 1 month or longer after initiation of the treatment regimen.
  • measurement of hair follicles in accordance with the foregoing is 11 days, 12 days, 13 days, 14 days, or 15 days, after initiation of the treatment regimen. In a particular embodiment, measurement of hair follicles in accordance with the foregoing is based on a skin biopsy taken 11 days, 12 days, 13 days, 14 days, or 15 days, after initiation of the treatment regimen.
  • measurement of hair follicles in accordance with the foregoing provides a means for evaluating success of a method of integumental perturbation (optionally in combination with post-perturbation treatment).
  • success of a method of integumental perturbation is determined based on a measured increase in total hair follicles in an area of skin subjected to integumental perturbation, for example, compared to an area of skin that was not subjected to the integumental perturbation step.
  • success of a method of integumental perturbation is determined based on a measured increase in activated or stimulated hair follicles, such as NL, PEL, or PELA follicular structures, in an area of skin subjected to integumental perturbation, for example, compared to an area of skin that was not subjected to the integumental perturbation step.
  • a desired increase in hair follicles or activated or stimulated hair follicles
  • the treatment is discontinued.
  • integumental perturbation is repeated.
  • integumental perturbation is repeated using a different method (for example, switching from a nonmechanical to a mechanical means or vice versa, or switching from laser to dermabrasion or vice versa, or switching to chemical perturbation using an inflammatory agent).
  • integumental perturbation is repeated but to a greater skin depth, for example, increasing the depth by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 microns or more.
  • measurement of hair follicles in accordance with the foregoing provides a means for evaluating whether a subject is a candidate for treatment, or continued treatment, with the methods described herein.
  • candidacy is established based on a measured increase in total hair follicles in an area of skin subjected to integumental perturbation (optionally in combination with post-perturbation treatment), for example, compared to an area of skin that was not subjected to the integumental perturbation step.
  • candidacy is established based on a measured increase in activated hair follicles, such as NL, PEL, or PELA follicular structures, in an area of skin subjected to integumental perturbation (optionally in combination with post-perturbation treatment), for example, compared to an area of skin that was not subjected to the integumental perturbation step.
  • a desired increase in hair follicles or activated hair follicles
  • treatment of that particular subject is discontinued.
  • integumental perturbation is repeated.
  • integumental perturbation is repeated using a different method (for example, switching from a nonmechanical to a mechanical means or vice versa, or switching from laser to dermabrasion or vice versa, or switching to chemical perturbation using an inflammatory agent).
  • integumental perturbation is repeated but to a greater skin depth, for example, increasing the depth by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 microns or more.
  • a method of treatment is carried out over a small area of skin (e.g ., 1x1 cm, or 1.5x1.5 cm, or 2x2 cm, or 2.5x2.5 cm, or 3x3 cm or more), hair follicles are measured in accordance with these methods, and if candidacy is established, the method of treatment is carried out over a larger area of skin, such as, e.g, an entire balding area of scalp.
  • a small area of skin e.g ., 1x1 cm, or 1.5x1.5 cm, or 2x2 cm, or 2.5x2.5 cm, or 3x3 cm or more
  • hair follicles are measured in accordance with these methods, and if candidacy is established, the method of treatment is carried out over a larger area of skin, such as, e.g, an entire balding area of scalp.
  • a treatment regimen described herein increases the anagen-to-telogen ratio by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment described herein increases the anagen-to-telogen ratio by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein increases the anagen-to-telogen ratio by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a treatment with one or more hair growth-promoting agents described herein increases the anagen-to-telogen ratio by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • Such an increase in the anagen-to-telogen ratio may be measured within or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or one year or longer after initiation of the treatment regimen.
  • success of treatment is assessed by measuring hair count in a treated area of skin.
  • detectable hairs can be quantified by photography, e.g., by global photographic recording or phototrichographic analysis (as described in, e.g., Uno et al., 2002, Acta Venereol 82:7-12 , incorporated herein by reference). Further, changes in the hair shaft thickness of photographically detectable hairs can be determined. In certain embodiments, the permanence of the hair growth is monitored over a time period of at least 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 4 years, or at least 5 years or more.
  • a treatment regimen described herein increases hair count by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • a treatment regimen described herein increases vellus hair by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • a treatment regimen described herein increases terminal hair by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • a treatment regimen described herein results in 1-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-75%, or 75-100% conversion of vellus hair to nonvellus ( i.e ., intermediary or terminal hair).
  • a treatment regimen described herein increases hair thickness by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • a treatment regimen described herein increases hair shaft diameter by approximately 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 15, 20, 25, or 30 microns or more.
  • a treatment regimen described herein increases mean hair shaft diameter by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • a treatment regimen described herein results in 1-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-75%, or 75-100% increase in mean hair shaft diameter.
  • a treatment regimen described herein increases the ratio of terminal to vellus hair follicles by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • Such an improvement in hair count, vellus hair, terminal hair, conversion of vellus hair to nonvellus ( e.g ., intermediate or terminal) hair, hair thickness, hair shaft diameter, or the ratio of terminal to vellus hair may be measured within or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or one year or longer after initiation of the treatment regimen.
  • an integumental perturbation treatment described herein increases hair count by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment described herein increases vellus hair by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment described herein increases terminal hair by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment described herein results in 1-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-75%, or 75-100% conversion of vellus hair to nonvellus ( i . e ., intermediary or terminal hair).
  • an integumental perturbation treatment described herein increases hair thickness by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment herein increases hair shaft diameter by approximately 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 15, 20, 25, or 30 microns or more.
  • an integumental perturbation treatment described herein increases hair shaft diameter by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment described herein increases the ratio of terminal to vellus hair follicles by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • Such an improvement in hair count, vellus hair, terminal hair, conversion of vellus hair to nonvellus (e.g ., intermediate or terminal) hair, hair thickness, hair shaft diameter, or the ratio of terminal to vellus hair may be measured within or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or one year or longer after initiation of the treatment regimen.
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein increases hair count by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein increases vellus hair by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein increases terminal hair by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein results in 1-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-75%, or 75-100% conversion of vellus hair to nonvellus ( i.e ., intermediary or terminal hair).
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein increases hair thickness by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein increases hair shaft diameter by approximately 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 15, 20, 25, or 30 microns or more.
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein increases hair shaft diameter by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a post-perturbation treatment described herein increases the ratio of terminal to vellus hair follicles by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • Such an improvement in hair count, vellus hair, terminal hair, conversion of vellus hair to nonvellus (e.g ., intermediate or terminal) hair, hair thickness, hair shaft diameter, or the ratio of terminal to vellus hair may be measured within or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or one year or longer after initiation of the treatment regimen.
  • an integumental perturbation treatment in combination with a treatment with one or more hair growth-promoting agents described herein increases hair count by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a treatment with one or more hair growth-promoting agents described herein increases vellus hair by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a treatment with one or more hair growth-promoting agents described herein increases terminal hair by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a treatment with one or more hair growth-promoting agents described herein results in 1-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-75%, or 75-100% conversion of vellus hair to nonvellus ( i.e., intermediary or terminal hair).
  • an integumental perturbation treatment in combination with a treatment with one or more hair growth-promoting agents described herein increases hair thickness by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • a treatment regimen described herein increases hair shaft diameter by approximately 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 15, 20, 25, or 30 microns or more.
  • an integumental perturbation treatment in combination with a treatment with one or more hair growth-promoting agents described herein increases hair shaft diameter by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • an integumental perturbation treatment in combination with a treatment with one or more hair growth-promoting agents described herein increases the ratio of terminal to vellus hair follicles by 5% or more, by 10% or more, by 15% or more, by 20% or more, by 25% or more, by 30% or more, by 40% or more, by 50% or more, by 75% or more, or by 100% or more.
  • Such an improvement in hair count, vellus hair, terminal hair, conversion of vellus hair to nonvellus (e.g ., intermediate or terminal) hair, hair thickness, hair shaft diameter, or the ratio of terminal to vellus hair may be measured within or after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or one year or longer after initiation of the treatment regimen.
  • the increase in hair count, vellus hair, terminal hair, conversion of vellus hair to nonvellus (e.g ., intermediate or terminal) hair, hair thickness, hair shaft diameter, and/or the ratio of terminal to vellus hair is observed in the treated area, for example, in an area of skin that was treated with integumental perturbation.
  • the increase in hair count, vellus hair, terminal hair, conversion of vellus hair to nonvellus (e.g ., intermediate or terminal) hair, hair thickness, hair shaft diameter, and/or the ratio of terminal to vellus hair is observed adjacent to the treated area.
  • the increase in hair count, vellus hair, terminal hair, conversion of vellus hair to nonvellus (e.g ., intermediate or terminal) hair, hair thickness, hair shaft diameter, and/or the ratio of terminal to vellus hair is observed in and adjacent to the treated area.
  • a synergistic effect of a combination of one or two or three or four or more treatments described herein may be measured as an improvement over a control subject (or a control skin site on the same subject) receiving fewer of the treatments.
  • treatment with a hair growth-promoting agent for 1 year or more, 8 months, 6 months, 3 months, 2 months, 1 month, 3 weeks, 2 weeks, 1 week or for a lesser period prior to integumental perturbation enhances the efficacy of the integumental perturbation treatment (either alone or in combination with other treatments described herein).
  • treatment with a hair growth-promoting agent for 1 year or more, 8 months, 6 months, 3 months, 2 months, 1 month, 3 weeks, 2 weeks, 1 week or for a lesser period or longer period following integumental perturbation enhances the efficacy of the integumental perturbation treatment (either alone or in combination with other treatments described herein).
  • enhanced efficacy of treatment with integumental perturbation (either alone or in combination with other treatments described herein) followed by treatment with a hair growth-promoting agent described herein, compared to treatment with integumental perturbation alone (or in combination with other treatments described herein) is measured as an increase in counts of nonvellus hairs and vellus hairs.
  • enhanced efficacy of treatment with integumental perturbation (either alone or in combination with other treatments described herein) followed by treatment with a hair growth-promoting agent described herein, compared to treatment with integumental perturbation alone (or in combination with other treatments described herein) is measured as an increase in counts of nonvellus hairs and vellus hairs.
  • measurement of hair in accordance with the foregoing provides a means for evaluating whether a subject is a candidate for treatment, or continued treatment, with the methods described herein.
  • Such measurement may be at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more after initiation of the treatment regimen, or after initiation of a particular step of the treatment regimen. In one embodiment, such measurement is 2, 3, or 4 months after the integumental perturbation step.
  • candidacy is established based on a measured increase in hair (e.g ., total hair, or vellus hair, or nonvellus hair) in an area of skin subjected to integumental perturbation (optionally in combination with post-perturbation treatment, optionally in combination with hair growth-promoting agent(s) treatment), for example, compared to an area of skin that was not subjected to the treatment step(s).
  • a measured increase in hair e.g ., total hair, or vellus hair, or nonvellus hair
  • integumental perturbation optionally in combination with post-perturbation treatment, optionally in combination with hair growth-promoting agent(s) treatment
  • candidacy is established based on a measured increase in hair (e.g ., total hair, or vellus hair, or nonvellus hair) in an area of skin subjected to integumental perturbation (optionally in combination with post-perturbation treatment, optionally in combination with hair growth-promoting agent(s) treatment), for example, compared to an area of skin that was not subjected to the integumental perturbation step.
  • a desired increase in hair is not observed
  • treatment of that particular subject is discontinued.
  • integumental perturbation and/or the post-perturbation treatment and/or treatment with hair growth-promoting agent(s) is repeated.
  • integumental perturbation is repeated using a different method (for example, switching from a nonmechanical to a mechanical means or vice versa, or switching from laser to dermabrasion or vice versa, or switching to chemical perturbation using an inflammatory agent).
  • integumental perturbation is repeated but to a greater skin depth, for example, increasing the depth by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 microns or more.
  • the subject is switched to a different post-perturbation treatment, for example, a topical composition comprising an inflammatory agent or pharmacologic modulator of hair follicle development.
  • a different hair growth-promoting agent treatment for example, an increased dose of agent, or treatment with a different agent (for example, switching from minoxidil to finasteride or vice versa, or switching from minoxidil to latanoprost or vice versa, or switching from minoxidil alone to a combination of minoxidil and finasteride or a combination of minoxidil and latanoprost, etc .).
  • a method of treatment is carried out over a small area of skin (e.g., 1x1 cm, or 1.5x1.5 cm, or 2x2 cm, or 2.5x2.5 cm, or 3x3 cm or more), hair is measured in accordance with a foregoing methods, and if candidacy is established, the method of treatment is carried out over a larger area of skin, such as, e.g, an entire balding area of scalp.
  • a small area of skin e.g., 1x1 cm, or 1.5x1.5 cm, or 2x2 cm, or 2.5x2.5 cm, or 3x3 cm or more
  • hair is measured in accordance with a foregoing methods, and if candidacy is established, the method of treatment is carried out over a larger area of skin, such as, e.g, an entire balding area of scalp.
  • hair follicles are characterized according to the following criteria for structures of interest (SOIs):
  • these criteria are derived from the flow chart / algorithm for categorizing the structures of interest outlined in Figure 31.
  • the following specific protocol for obtaining and categorizing structures of interest is used:
  • SOI structures of interest
  • a SOI attached to another pilosebaceous unit that extended to the epidermis is classified as a preexisting-like attached (PELA).
  • Unattached SOIs are then classified based on the presence of a dermal channel, shaft (small or large), sebaceous gland (small or large), and/or pore (small or large).
  • One or more large traits or two or more small traits result in the SOI being classified as PEL, while only one small trait results in the SOI being classified as NL.
  • SOIs that have neither a dermal channel, shaft, sebaceous gland, or pore and are not attached to another pilosebaceous unit are stained for AP, Ki67, Ber-EP4, and elastin.
  • SOIs are categorized based on their marker expression: presence or absence of alkaline phosphatase activity (DP marker); presence or absence of Ki67 (proliferation marker); presence or absence of Ber-EP4 (hair follicle marker); and presence or absence of dermal channels (extracellular matrix marker visualized with elastin).
  • SOIs that do not have a dermal channel are classified as NL, while those that have a dermal channel are classified as PEL.
  • SOIs that are Ber-EP4-negative are classified as non-follicular.
  • NLs and PELs are refined into further categories: with or without DP (positive or negative AP staining); and active or inactive (positive or negative Ki67 staining).
  • Inconclusive staining for Ber-EP4 is treated as a positive result for Ber-EP4, and inconclusive staining for alkaline phosphatase or Ki67 results in the SOI categorized as an NL (no dermal channel present) or a PEL (dermal channel present).
  • CM Scanning laser confocal microscopy
  • This fluid immersion microscope requires oil / water immersion to measure changes in the index of refraction within the tissue as detected by the reflected laser light.
  • Real-time noninvasive confocal infrared imaging of the epidermis, papillary dermis, and superficial reticular dermis to a maximum depth of 350 ⁇ m is possible with resolution comparable to conventional light microscopy. Skin can be imaged in its native state without the fixing, sectioning, and staining necessary for histology. As such, dynamic processes can be noninvasively observed over an extended period of time.
  • Reflectance confocal microscopy may differentiate acute allergic and irritant contact dermatitis in vivo, J Am Acad Dermatol 50 (2004), pp. 220-228 ; Aghassi, et al., Time-sequence histologic imaging of laser-treated cherry angiomas with in vivo confocal microscopy, J Am Acad Dermatol 43 (2000), pp. 37-41 ; and Gonzalez et al. Non-invasive (real-time) imaging of histologic margins of a proliferative skin lesion. In Vivo. J Invest Dermatol 1998 111: 538-539 .
  • confocal microscopy is performed using a device (Vivascope; Lucid, Inc.) used for human studies.
  • An exemplary protocol follows, which may be optimized as deemed necessary by the practitioner. Subjects are positioned in an inclined or sitting position to allow visualization of the treated area of the scalp. Each subject remains still in the imaging position for a minimum of 15 minutes of imaging per subject. A medical grade adhesive secures the fluid immersion ring to the surface of the skin. The ring remains attached throughout the imaging session and a new ring is applied on each test site.
  • CM is performed on Day 0, 7, and 14 (11 and 17 if punch biopsy was not taken on Day 14) following the beginning of the treatment regimen.
  • the safety and efficacy of a treatment described herein for scarring alopecia may be measured using the methods described in herein.
  • successful treatment is determined as an increase in the number of visually or photographically detected hairs.
  • successful treatment is evaluated by a skin biopsy for hair follicle structures and scar attributes.
  • treatment is continued until the symptoms and signs of scalp inflammation are controlled, and progression of the condition has been halted.
  • scalp inflammation is measured by biopsy of the scalp.
  • treatment is continued until, e.g ., itching, burning, pain, and tenderness have cleared, scalp redness, scaling, and/or pustules are no longer present, and the hair loss has not extended.
  • cicatricial alopecias may reactivate after a quiet period, and treatment may have to be repeated at the reemergence of symptoms or signs of the condition.
  • the objective of the following protocol is to determine the effects of dermabrasion on inducing the formation of neogenic or neogenic-like hair follicles in human skin.
  • patients for the following protocol may be Caucasian males 20-50 years of age, have androgenetic alopecia with the presence of a transition zone defined as an area possessing both terminal and miniaturized hairs, have a Fitzpatrick skin type 1-4 (higher Fitzpatrick skin type ratings are not preferred due to the increased risk of keloid formation and hypopigmentation in these subjects).
  • Patients for whom treatment may be contraindicated are those who are currently participating in or have participated in any clinical study with an investigational drug within the thirty (30) days immediately preceding treatment, with current or recent use ( ⁇ 1 y) of isotretinoin (Accutane), currently taking hormone therapy, or steroids or other immunomodulators or have taken these medications within the past thirty (30) days (inhaled steroids are acceptable), currently using Rogaine or Propecia or used them in the past forty-five (45) days, immune compromised or undergoing therapy to treat an immune disorder, have a clinically significant medical condition that may interfere with the protocol described herein, have other active skin diseases (such as actinic keratosis or psoriasis) or skin infections (bacterial, fungal or viral, esp.
  • other active skin diseases such as actinic keratosis or psoriasis
  • skin infections bacterial, fungal or viral, esp.
  • HSV infection in the area to be treated, have a history of keloids or hypertrophic scarring, hypersensitivity to lidocaine, poor wound healing, diabetes, or coagulopathy, undergoing current drug or alcohol abuse, psychiatric dysfunction, or other factors that would limit compliance, have sunburned skin, or who are currently taking anti-platelet agents other than aspirin.
  • Dermabrasion using alumina particles is performed on Day 0. Dermabrasion is performed to a depth of approximately 100 ⁇ m, which includes removal of epidermis and disruption of the papillary dermis (detectable by a shiny, whitish appearance) inducing the formation of small pinpoints of blood in the treated area. Dermabrasion is performed in two sites of the scalp skin corresponding to transitional areas (or advancing margin) of balding in the vertex region. The area is then allowed to heal without manipulation. 4 mm punch biopsies are performed either on day 11 or 14, and structures associated with hair follicles are examined in these subjects based on histological assessment. A third biopsy is optionally performed on Day 14 on an untreated area 1 cm away from the treated area to serve as histologic control.
  • the protocol may be amended in accordance with the findings. For example, if dermabrasion causes presence of neogenic-like hair follicles in a 4 mm punch biopsy in, for example, at least three of the first 15 patients, then additional patients will be treated in two sites: one site corresponding to the area of greatest balding on the vertex and one site corresponding to a transitional area (or advancing margin) of balding in the vertex region.
  • Two sites on each subject's scalp are identified for treatment, both corresponding to transitional areas (or advancing margins) of balding in the vertex region. Some patients may be treated in a site of greatest balding on the vertex region.
  • the procedure begins with shaving/clipping of the existing hair in the area to be treated followed by a thorough cleaning with antiseptic cleansing agent.
  • Numbing agents such as lidocaine HCL 2% and Epinephrine 1:100,000, are injected to anesthetize the surface to be treated. Dermabrasion is performed to a depth of approximately 100 ⁇ m, which includes removal of epidermis and disruption of the papillary dermis (detectable by a shiny, whitish appearance) inducing the formation of small pinpoints of blood in the treated area.
  • Each dermabraded area is approximately a 1.5 cm x 1.5 cm square.
  • Suitable devices for dermabrasion are the ASEPTICO ECONO-DERMABRADER from Tiemann and Company, the DX system from Advanced Microderm (see, e.g., http://www.advancedmicroderm.com/products/tech-specs.html), or the M2-T system from Genesis Biosystems.
  • Adhesive ocular shields are worn by the patient during the procedure to avoid complications due to aluminum crystals entering the eye (chemosis, photofobia, punctuate keratitis) and the doctor should wear safety goggles.
  • the dermabrasion tool is carefully maneuvered over the area to carefully remove layers of skin until the desired level is reached. The procedure usually takes only a few minutes, up to about a half hour.
  • patients should be asked to: not wear contact lenses during the procedure, discontinue use of over the counter exfoliation products such as Retinol, Glycolic or other hydroxy acids, Salicylic acid, Beta hydroxyl acids 3 days prior to treatment, discontinue use of retinoids 30 days prior to treatment, not receive Botox or collagen injections for 2 weeks prior to treatment.
  • over the counter exfoliation products such as Retinol, Glycolic or other hydroxy acids, Salicylic acid, Beta hydroxyl acids 3 days prior to treatment, discontinue use of retinoids 30 days prior to treatment, not receive Botox or collagen injections for 2 weeks prior to treatment.
  • the treated skin will be red, swollen and tender, and the wound should be cared for as follows until new skin starts to grow; this usually takes 7-10 days: 1) Keep the area clean and dry for today. Do not cover, bandage, or otherwise manipulate the treated area; 2) Avoid touching the area when washing hair; 3) Pat the area dry. Do not cover, bandage, or otherwise manipulate the treated area.
  • the treated are may itch as the new skin grows and may be slightly swollen, sensitive, and bright pink for several weeks after dermabrasion.
  • the procedure begins with thoroughly cleaning the area to be biopsied with antiseptic cleansing agent.
  • Lidocaine HCL 2% and Epinephrine 1:100,000 (approximately 0.5 cc to each site) are injected to anesthetize the site that will be biopsied.
  • 4 mm punch biopsy is performed.
  • the biopsied site is closed with 2 4.0 Ethalon sutures.
  • Vaseline and band-aid are applied. Tissue samples are stored in formalin for histological analysis.
  • the factors to be evaluated when determining success of treatment are the presence or absence of: crusting/scabbing; comedones; infection; pigmentary changes (e.g ., absent, hypopigmentation (mild, moderate or severe), or hyperpigmentation (mild, moderate or severe)); scarring; re-epithelialization; or presence of hair follicles by gross observation.
  • a clinical study was carried out in accordance with the protocol described above.
  • the goal of the clinical study was to examine whether dermabrasion involving removal of epidermis and some papillary dermis could induce hair follicles in human scalp.
  • PMDA particle-mediated dermabrasion
  • Digital photography of the dermabraded areas was done at baseline, and on any of the post-PMDA days that the subject returned to clinic; e.g., on days 7, 11, 14, 17, 24, and 60 or other intervening days if subjects returned on a non-scheduled day.
  • tattooing was done with a 4 mm long 28 gauge needle at two points at diagonally opposite corners of a 1.5 cm x 1.5 cm square in the scalp sites.
  • a template of sterile (plastic) material was used to guide the tattooing.
  • Tattoos were used to register the photographs obtained at different times throughout the study.
  • High resolution close up digital images (NikonTM DL series camera), using tattoos for registration, were used to record the visible aspects of the wound and the healing process.
  • PMDA particle-mediated dermabrasion
  • DX system from Advanced MicrodermTM
  • All subjects were given ocular protection and anesthesia for the procedure.
  • the procedure began with shaving/clipping of the existing hair in the area to be treated, followed by a thorough cleaning with antiseptic cleansing agent.
  • Lidocaine HCL 2% plus Epinephrine 1:100,000 was injected to anesthetize the surface that was treated.
  • PMDA was performed to a depth of approximately 100 ⁇ m, that included removal of epidermis and disruption of the papillary dermis (detectable by a shiny, whitish appearance) inducing the formation of small pinpoints of blood in the treated area.
  • Each of the two dermabraded areas was approximately 1.5 cm x 1.5 cm square. Subjects were instructed to allow the area to heal without manipulation. The scab resulting from the PMDA generally detached six-ten days after PMDA. Locations of dermabraded areas are listed in Table 2 below. Table 2.
  • Scalps were visually examined on any or all of the following days: baseline, any suture removal day, days 7, 11, 14 and 60, and the following characteristics analyzed: crusting/scabbing, comedones, infection, pigmentary changes, scarring, re-epithelialization, and the presence of hair follicles by gross observation.
  • the timing and results of the scalp examinations for each subject can be found in Table 4. Table 4.
  • neogenic-like hair follicles was evaluated in biopsy specimens using routine histological techniques.
  • General morphological parameters including presence or absence of a hair pore, presence or absence of a hair shaft, and presence or absence of a sebaceous gland, were assessed from sections stained by hematoxylin and eosin (H&E). The presence of elastin fibers was determined using the Luna stain.
  • Immunohistochemistry was performed using antibodies against BerEP4 (a marker of embryonic hair follicles) and Ki67 (a marker of cell proliferation). Alkaline phosphatase (AP) histochemistry was used to identify the dermal papilla of the HF.
  • Neogenic-like hair follicles were characterized by using some or all of the following criteria: hairs that were of 1) shorter length than vellus and/or vellus-like hair follicles, 2) had lack of a connection with a pre-existing pilosebaceous unit, 3) had lack of a pore at the skin surface, 4) had lack of a well-differentiated sebaceous gland, 5) had lack of a hair shaft, 6) had lack of an elastin-negative "streamer” or "dermal channel,” and 7) had positive staining for alkaline phosphatase, BerEP4 (a marker of embryonic hair follicles), and Ki67 (a marker of cell proliferation).
  • the time at which neogenic-like follicles can be detected after PMDA was also considered. Twenty-seven (27) of the biopsies were obtained on day fourteen (fourteen days after PMDA). The two subjects (#3 and #5) in whose biopsies evidence of neogenic-like hair follicles each had biopsies on day fourteen. There were also 23 biopsies negative for neogetuc-like hair follicles on day 14 (seven right sided PMDA areas; ten left sided PMDA areas; six control areas). Biopsies on day ten (three biopsies), day eleven (one biopsy), day thirteen (one biopsy), and day 20 (one biopsy) were negative for neogenic-like hair follicles. All ten biopsies done in control areas often subjects (non-dermabraded) were negative for neogenic-like hair follicles (one on day thirteen, six on day fourteen, one on day 20, and two on unknown dates).
  • the objective of this study is to assess the effects of three laser treatments as a method of integumental perturbation compared to dermabrasion on promoting hair growth, as evidenced, e.g ., by hair follicle activation, stimulation, or reorganization, and/or neogenesis in human skin.
  • patients selected for treatment in the study may be Caucasian males 20-50 years of age, have androgenetic alopecia with the presence of a transition zone defined as an area possessing both terminal and miniaturized hairs, have a Fitzpatrick skin type 1-4 (higher Fitzpatrick skin type ratings are not preferred due to the increased risk of keloid formation and hypopigmentation in these subjects).
  • Patients for whom treatment may be contraindicated are those who are currently participating in or have participated in any clinical study with an investigational drug within the thirty (30) days immediately preceding treatment, with current or recent use ( ⁇ 1 y) of isotretinoin (Accutane), currently taking hormone therapy, or steroids or other immunomodulators or have taken these medications within the past thirty (30) days (inhaled steroids are acceptable), currently using Rogaine or Propecia or used them in the past forty-five (45) days, immune compromised or undergoing therapy to treat an immune disorder, have a clinically significant medical condition that may interfere with the protocol described herein, have other active skin diseases (such as actinic keratosis or psoriasis) or skin infections (bacterial, fungal or viral, esp.
  • other active skin diseases such as actinic keratosis or psoriasis
  • skin infections bacterial, fungal or viral, esp.
  • HSV infection in the area to be treated, have a history of keloids or hypertrophic scarring, hypersensitivity to lidocaine, poor wound healing, diabetes, or coagulopathy, undergoing current drug or alcohol abuse, psychiatric dysfunction, or other factors that would limit compliance, have sunburned skin, or who are currently taking anti-platelet agents other than aspirin.
  • Eligible subjects will be recruited into the trial without randomization.
  • Four 1.5 cm X 1.5 cm treatment sites will be selected on the left and right, of the anterior and posterior transitional area of the scalp. The sites will be designated - left anterior, left posterior, right anterior, right posterior. All four sites will correspond to transitional areas (or advancing margins) of balding in the anterior or posterior scalp. The method of integumental perturbation to be used at each site will be randomly assigned.
  • the four methods of integumental perturbation will be performed to a various depths that will include removal of the entire epidermis and disruption of the papillary dermis and may induce the formation of small pinpoints of blood in the treated area.
  • the surgeon will perform each integumental perturbation according to the randomization schedule in each of the treatment sites along the transitional areas (or advancing margin) of balding scalp on Day 0.
  • the subject will be instructed to allow the area to heal without manipulation.
  • Subjects will be asked to come back to undergo a 4 mm punch biopsy on Day 14.
  • a single follow visit will be made at Day 28 to document healing of the punch biopsy, suture removal, and collect any adverse events.
  • the presence of new hair, and evidence of new, activated, or reorganized follicles will be histologically examined. This exploratory trial design structure will provide a greater likelihood of observing meaningful hair growth or hair follicle activation, reorganization, or neogenesis after these various methods of integumental perturbation, if they
  • patients Prior to integumental perturbation, patients should be asked to: not wear contact lenses during the procedure. discontinue use of over the counter exfoliation products such as Retinol, Glycolic or other hydroxy acids, Salicylic acid, Beta hydroxyl acids 3 days prior to treatment, discontinue use of retinoids 30 days prior to treatment, not receive Botox or collagen injections for 2 weeks prior to treatment.
  • over the counter exfoliation products such as Retinol, Glycolic or other hydroxy acids, Salicylic acid, Beta hydroxyl acids 3 days prior to treatment
  • discontinue use of retinoids 30 days prior to treatment not receive Botox or collagen injections for 2 weeks prior to treatment.
  • Numbing agents such as lidocaine HCL 2% and Epinephrine 1:100,000, are injected to anesthetize the surface to be treated.
  • the treated skin could be red, swollen and tender, and the wound should be cared for as follows until new skin starts to grow; this usually takes 7-10 days: 1) Keep the area clean and dry for today. Do not cover, bandage, or otherwise manipulate the treated area; 2) Avoid touching the area when washing hair; 3) Pat the area dry. Do not cover, bandage, or otherwise manipulate the treated area.
  • the treated area may itch as the new skin grows and may be slightly swollen, sensitive, and bright pink for several weeks after dermabrasion.
  • Standard dermabrasion is performed to a depth of approximately 100 ⁇ m, which includes removal the entire epidermis and disruption of the papillary dermis (detectable by a shiny, whitish appearance) inducing the formation of small pinpoints of blood in the treated area.
  • Each dermabraded area is approximately a 1.5 cm x 1.5 cm square.
  • Suitable devices for dermabrasion are the ASEPTICO ECONO-DERMABRADER from Tiemann and Company, the DX system from Advanced Microderm (see, e.g., http://www.advancedmicroderm.com/products/tech_spees.html), or the M2-T system from Genesis Biosystems.
  • Adhesive ocular shields are worn by the patient during the procedure to avoid complications due to aluminum crystals entering the eye (chemosis, photofobia, punctuate keratitis) and the doctor should wear safety goggles.
  • the dermabrasion tool is carefully maneuvered over the area to carefully remove layers of skin until the desired level is reached. The procedure usually takes only a few minutes.
  • An Ultrapulse (fractional mode) CO 2 laser will be used to disrupt the epidermis and dermis to approximately 100 to 500 ⁇ m in depth.
  • the Ultrapulse laser produces an effect that is similar to that of dermabrasion yet the integumental perturbation delivers a greater amount of energy deeper into the skin in a non-scaring fractional ablation.
  • the treated area is approximately 1.5 cm x 1.5 cm square.
  • the Ultrapulse will be set to deliver up to 350 mJ, up to 52.5 Watts, using pattern size #8, density #4, and fill the square treatment site with up to 5 passes.
  • An Ultrapulse CO 2 laser (ablative mode) will be used to disrupt the epidermis and dermis to approximately 100 to 500 ⁇ m in depth.
  • the Ultrapulse laser produces an effect that is similar to that of dermabrasion yet this method of integumental perturbation delivers a greater amount of energy deeper into the skin in a non-scaring ablation that resembles the dermabrasion.
  • the treated area is approximately 1.5 cm x 1.5 cm square.
  • the Ultrapulse will be set to deliver up to 500 mJ in 1 msec, 1 Watts, using a spot size of 3 mm at 2 Hz to fill the square treatment site may require up to 15 passes.
  • the ablative erbium laser will be set to deliver up to 5 Joules 240 msec in of energy at level 3 so that in up to 15 passes it will produce skin disruption up to a depth of 500 ⁇ m.
  • the treated area is approximately 1.5 cm x 1.5 cm square.
  • the procedure begins with thoroughly cleaning the area to be biopsied with antiseptic cleansing agent.
  • Lidocaine HCL 2% and Epinephrine 1:100,000 (approximately 0.5 cc to each site) are injected to anesthetize the site that will be biopsied.
  • 4 mm punch biopsy is performed. Biopsied site is closed with 2 4.0 Ethalon sutures.
  • Vaseline and band-aid are applied. Tissue samples are stored in formalin for histological analysis.
  • the treated subjects will be asked to return ten days after undergoing the biopsy. During this visit the following procedures and evaluations will be performed: suture removal, assessment of the treated areas, photography of treated areas, review of the subject's medical history and concomitant medications, documentation of adverse events, final evaluation.
  • the primary endpoint is the number of neogenic-like hair follicle structures as determined by histologic analysis of the 4 mm punch biopsies on Study Day 14.
  • Figure 23F provides an image of the skin's epidermal ridges that enclose the vascularized dermal papillae and can help to illustrate how integumental perturbation, e.g ., by dermabrasion to a depth of 100-150 microns, would cause pinpoint bleeding.
  • Table 7. Treatment Hair Follicle Type (NL or PEL) All Hair Follicles All NL All PEL Dermabrasion 18 27 45 Fractional Laser 12 16 28 Ultrapulse Laser 7 11 18 Smoothpeel Laser 8 8 16 Totals 45 62 107
  • This example provides a clinical protocol to examine the use of integumental perturbation to promote hair growth, as evidenced, e.g., by hair follicle activation, stimulation, or reorganization, and/or neogenesis and/or by increased numbers of vellus and/or terminal hair counts and/or hair shaft thickness in human skin in male subjects with androgenetic alopecia.
  • the two methods that will be used include the more superficial form of integumental perturbation with dermabrasion and the deeper (extending to the level of the subcutaneous fat) full thickness skin excision using punch biopsy.
  • integumental perturbation also referred to in this section as "controlled perturbation”
  • the controlled perturbation can be more superficial (e.g . with a dermabrasion affecting mostly the epidermis) or can be deeper ( e.g . when a punch biopsy affects both the epidermis and the deeper dermis). It is possible that this type of stimulation may lead to macroscopic evidence of hair growth.
  • the following protocol describes a Phase Ila clinical study that evaluated the effect of dermabrasion and post-perturbation treatment with a hydrogel (comprising Carbomer (Carbopol 980), glycerol, sodium hydroxide, methylparaben, propylparaben, and purified water) on (i) the formation of neogenic-like or activated or stimulated hair follicle structures (e.g., NL, PEL and PELA as described in Section 5.8.4.1 supra) and (ii) hair growth.
  • Carbomer Carbopol 980
  • glycerol glycerol
  • sodium hydroxide sodium hydroxide
  • methylparaben methylparaben
  • propylparaben propylparaben
  • purified water purified water
  • Diagnosis and main criteria for inclusion are Caucasian males 20-65 years of age, providing written informed consent, who have androgenetic alopecia with the presence of a vertex transition zone defined as an area possessing both terminal and miniaturized hairs, Hamilton-Norwood type 3V, 4, 5, 5A, or 5V, with a vertex area large enough to accommodate both treatment sites, and Fitzpatrick skin type 1-4.
  • Photographic fields of measurement include the Total Analysis Area, which is a 1.13 cm 2 circular region in an area that is dermabraded on Day 0, treated with hydrogel, undergoes a 4 mm punch biopsy on Day 14, and then receives additional treatment with hydrogel.
  • the Total Analysis Area there is the Circular Biopsy Area, which is a 0.13 cm 2 circular region that undergoes a 4 mm punch biopsy, and the Target Analysis Area, which is the Total Analysis Area minus the Circular Biopsy Area, which is a 1.00 cm 2 circular region that has received only dermabrasion.
  • Treatment in this study consists of two treatment modalities:
  • Subjects are scheduled to receive hydrogel for 31 days: treatment period 1 (Day 0 until 2 days prior to punch biopsy 1 [Day 11]) and treatment period 2 (Day 17 until end of treatment [Day 35]).
  • the dose of hydrogel is an approximate volume of 0.1 mL applied twice daily to two sites, for a total intended volume of 0.4 mL. Due to droplet size variability, this translates to an actual total volume range of 0.27 to 0.88 mL.
  • the planned duration of the study per subject is 196 days, comprising a 14 day screening period, and 182 days of treatment and follow-up.
  • the planned total duration of the study is approximately 12 months.
  • subjects will have Baseline photography that includes a pin-point tattoo and hair dye.
  • Two sites will be assigned, each measuring 1.5 cm x 1.5 cm and designated right (R) and left (L) with a minimal distance of 2 cm, identified in transitional areas of the balding vertex scalp, which has a very low density of terminal hairs.
  • the hair density of the 2 sites should be as similar as is possible.
  • Dermabrasion of two sites per subject will be carried out using a hand-held dermabrader with a standard grit diamond fraise to achieve pinpoint capillary bleeding (estimated depth 100 microns, and therefore not anticipated to cause scarring). After dermabrasion the hydrogel will be applied to the two sites.
  • the two dermabraded sites will receive a full thickness 4 mm skin punch biopsy that is allowed to heal by secondary intention without occlusion.
  • the 4 mm punch biopsies also provide a deeper perturbation that will be tested with hydrogel for the induction of neogenic-like follicles and other follicular structures of interest.
  • a second skin punch biopsy will be performed over the 2 dermabraded sites where there was a first punch biopsy on Day 14.
  • any scar tissue formed from the 4 mm punch biopsies on Day 14 will be excised by this second biopsy on Day 168, which will be closed by sutures.
  • the Day 168 punch of the dermabraded sites will be a 5 mm or 6 mm skin biopsy (or elliptical biopsy by hand, or with an excisor, of a similar size) in order to assure scar removal and photography tattoo removal.
  • the sutures are scheduled to be removed at a safety follow-up 2 weeks later (Day 182).
  • the sustained positive change in all hair at the 6 month time point is comprised in large part by the striking increase in hair follicles with shafts between 10-20 microns in diameter (widths measured photographically).
  • the increase in follicles with shafts between 20-30 microns has a small contribution to this overall positive change (see Table 14 ).
  • Table 8 Subject Demographics and Characteristics Demographics and Baseline Characteristics Treatment Group: Dermabrasion plus post-integumental perturbation treatment Age (years) N 33 Mean (SD) 43.1 (10.4) Median 43 Min : Max 22 : 64 No. (%) ⁇ 40 13 (39.4%) No. (%) > 40 20 (60.6%) Fitzpatrick Skin Type, No. (%) I 3 (9.1%) II 22 (66.7%) III 7 (21.2%) IV 1 (3.0%) Hamilton-Norwood Class, No.
  • Table 10 Photographic hair count of all hair on Day 168 in target analysis area subjected to dermabrasion plus hydrogel treatment Baseline Day 168 Change N 33 33 33 Mean (SE) 522.1 (28.82) 569.1 (32.38) 47.0 (14.75) % Change 9% Min: Max 185 : 885 302 : 1026 -99 : 218 90% CI* (22.01, 71.99) P-value* ⁇ 0.0016 * CI and P-value are results for within-group mean changes.
  • Table 11 Photographic hair count of non-vellus hair on Day 84 in target analysis area subjected to dermabrasion plus hydrogel treatment Baseline Day 84 Change N 33 33 33 Mean (SE) 358.7 (25.84) 406.3 (27.31) 47.6 (9.71) % Change 13% Min : Max 106 : 611 87 : 752 -39 : 190 90% CI* (31.15, 64.06) P-value* ⁇ 0.0001 * CI and P-value are results for within-group mean changes.
  • Table 12 Photographic hair count of non-vellus hair on Day 168 in target analysis area subjected to dermabrasion plus hydrogel treatment Baseline Day 168 Change N 33 33 33 Mean (SE) 358.7 (25.84) 365.2 (24.79) 6.5 (8.85) % Change 2% Min : Max 106: 611 90 : 635 -99 : 173 90% CI* (-8.51, 21.48) P-value* 0.2346 * CI and P-value are results for within-group mean changes.
  • Table 13 Photographic hair count of vellus hair on Day 84 in target analysis area subjected to dermabrasion plus hydrogel treatment Baseline Day 84 Change N 33 33 33 Mean* 163.4 169.1 5.8 % Change 4% *There are two 1 cm 2 TAHC sites per subject; hair counts are normalized for 1 cm 2 .
  • Table 14 Photographic hair count of vellus hair on Day 168 in target analysis area subjected to dermabrasion plus hydrogel treatment Baseline Day 168 Change N 33 33 33 Mean* 163.4 203.9 40.5 % Change 25% *There are two 1 cm 2 TAHC sites per subject; hair counts are normalized for 1 cm 2 .
  • Table 15 Vellus hair count and percent change from baseline by 10 micron intervals in target analysis area subjected to dermabrasion plus hydrogel treatment Diameter (microns) Baseline 3 Month Hair Count 3 Month Percent Change 6 Month Hair Count 6 Month Percent Change 20-30 2,962 2,998 1.22% 3,165 6.85% 10-20 2,383 2,554 7.18% 3,506 47.13% ⁇ 10 45 28 -37.78% 56 24.44% Subtotal 5,390 5,580 3.53% 6,727 24.81%
  • Table 16 Nonvellus hair count and percent change from baseline by 10 micron intervals in target analysis area subjected to dermabrasion plus hydrogel treatment Diameter (microns) Baseline 3 Month Hair Count 3 Month Percent Change 6 Month Hair Count 6 Month Percent Change 100+ 294 339 15.31% 297 1.02% 90-100 433 480 10.85% 464 7.16% 80-90 698 753 7.88% 699 0.14% 70-80 1,152 1,228 6.60% 1,109 -3.73% 60-70 1,500
  • This example describes a clinical protocol for combined treatment with dermabrasion (DA) and a hair growth-promoting agent (HGPA) or agents on hair growth.
  • the protocol may be carried out as a Phase 2a, open-label, mono-center, randomized study; in this case, subjects are randomized to have DA on the right or left side of the vertex scalp.
  • the DA/Hydrogel site plus HGPA is the experimental site; and the non-DA/Hydrogel site plus HGPA is the control site.
  • each subject acts as his own control.
  • Optional steps for including these controls in the protocol are provided throughout the description below.
  • Protocol 1 Commercially available Minoxidil foam (5%); 2 ml applied twice a day; the protocol is to be supported by prior irritancy studies (DA + Minoxidil). With respect to selecting a minoxidil treatment, Olsen et al. J Am Acad Dermatol 2007;57:767-74 and Olsen et al., J Am Acad Dermatol 2002;47:377-85 , each of which is incorporated herein by reference in its entirety, may be used as references. In a variation, a 5% solution or a 2% solution may be used. 5% minoxidil solution is approved for use in men in the US and Germany but not in women.
  • Latanoprost eye drops (0.005% formulation currently on the market): 1 dropper once a day. A 0.1% formulation with propylene glycol (20%) and ethanol (50%) will be used for this. Because Latanoprost can cause skin irritation, this protocol is to be supported by prior animal model studies of skin irritancy (DA and Non-DA sites). With respect to selecting a Latanoprost treatment, Blume-Peytavi et al., 2010, American Academy of Dermatology, doi:10.1016/j.jaad.2011.05.026, Epub Aug 27 2011 , incorporated by reference herein in its entirety and which compares latanoprost 0.1% solution to placebo, may be used as a reference.
  • subjects may receive HGPA treatment on DA and non-DA skin sites.
  • the reference treatment with be HGPA alone (i.e., on non-DA sites).
  • Treatment consists of two modalities: (i) DA/Hydrogel; and (ii) HGPA.
  • Subjects receive DA (or non-DA for controls), followed by application of Hydrogel (e . g ., the hydrogel described in the example of Section 10 below) for 11 days. Subsequently, topical application of HGPA will begin and continue for 24 weeks to: DA sites (and non-DA sites if applicable).
  • Subjects are treated for approximately 196 days, comprising a 14 day screening period, and 182 days of treatment and follow-up. The planned overall duration of treatment is approximately 12 months.
  • Diagnosis and eligibility for treatment Caucasian males 20-65 years of age who have androgenetic alopecia with the presence of a vertex transition zone defined as an area possessing both terminal and miniaturized hairs, Hamilton-Norwood type 3V, 4, 5, 5A, or 5V, and Fitzpatrick skin type 1-4.
  • a vertex transition zone defined as an area possessing both terminal and miniaturized hairs, Hamilton-Norwood type 3V, 4, 5, 5A, or 5V, and Fitzpatrick skin type 1-4.
  • subjects should have a vertex area large enough to accommodate both treatment sites.
  • Treatment sites measure at least 1.5 cm x 1.5 cm and are preferably located in transitional areas of the balding vertex scalp, which has a very low density of terminal hairs.
  • the two treatment sites can be designated, designated right (R) and left (L) with a minimal distance of 2 cm; the hair density of the two sites should be as similar as is possible; and in each subject, the site for DA is randomized to right or left; each subject is his own control: (i) DA/Hydrogel plus HGPA (experimental site); (ii) non-DA/Hydrogel plus HGPA (control site).
  • DA is performed using a hand-held dermabrader with a standard grit diamond fraise to achieve pinpoint capillary bleeding (estimated depth 100 microns, and therefore not anticipated to cause scarring).
  • DA hydrogel is applied to the DA site (and, for controls, a similar sized site on the opposite side of the scalp) for 11 days. See the scheme below for more details.
  • HGPA is begun on the DA treatment site (and, for controls, also on non-DA sites on the opposite side of the scalp). HGPA is applied continuously for 24 weeks; subjects return to the clinic on Day 84 and Day 168 for repeat photographic and clinical evaluations. Monthly safety follow-up phone calls may be performed on Days 28, 56, 112 and 140.
  • Diagnostic skin punch biopsies may be performed at the treated site (if controls are present, at both treated sites) to analyze follicular structures on, e.g., optionally on Days 84 and/or Day 168. Biopsy sites are sutured closed. The sutures are removed at a follow-up 2 weeks later.
  • the end of the protocol is defined as the last clinical visit of the last subject.
  • a photographic field of measurement (which may extend to two Analysis Areas if controls are included) may comprise a 1.13 cm 2 circular region in the site that was treated with HGPA (+/- DA).
  • HGPA applied topically to DA (and, if controls are present, non-DA) sites is monitored through the collection of data from targeted examination of the treated scalp sites and the reporting of adverse events.
  • Safety visits may be conducted on Days 1, 2, 3, 12, 15, 17, 18, 19, 20 and 182; visits on Days 3, 18, 19 and 20 may be replaced by calls if they fall on the weekend); additional or fewer days may be required depending on subject compliance. For example, subjects may be monitored for 4 weeks before letting them apply at home. Adverse events may also be reported at safety phone calls on Days 28, 56, 112 and 140. In addition liver and renal function, Hgb-A1C, and urinalysis are performed at screening and on Days 182. A physical examination is performed at screening and Day 182; vital signs and ECG are performed at screening. Vital signs are also measured on Days 0, 84 and 168 (when DA and photography are performed) and Day 182 (end of treatment protocol or at early termination).
  • the primary efficacy analysis is performed for the Full Analysis Set (all subjects who were enrolled and who received at least one dose of HGPA to the DA and Non-DA sites).

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